HOME

TheInfoList



OR:

The biochemistry of Alzheimer's disease, the most common cause of
dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
, is not yet very well understood.
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
(AD) has been identified as a
proteopathy In medicine, proteinopathy (; 'pref''. protein -pathy 'suff''. disease proteinopathies ''pl''.; proteinopathic ''adj''), or proteopathy, protein conformational disorder, or protein misfolding disease refers to a class of diseases in which certa ...
: a
protein misfolding In medicine, proteinopathy (; 'pref''. protein -pathy 'suff''. disease proteinopathies ''pl''.; proteinopathic ''adj''), or proteopathy, protein conformational disorder, or protein misfolding disease refers to a class of diseases in which certa ...
disease due to the accumulation of abnormally folded
amyloid beta Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...
(Aβ) protein in the
brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
. Amyloid beta is a short
peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...
that is an abnormal
proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
byproduct of the
transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
amyloid-beta precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse format ...
(APP), whose function is unclear but thought to be involved in neuronal development. The
presenilin Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset ...
s are components of proteolytic complex involved in APP processing and degradation. Amyloid beta
monomer In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification Mo ...
s are soluble and contain short regions of
beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a g ...
and polyproline II helix
secondary structure Protein secondary structure is the three dimensional conformational isomerism, form of ''local segments'' of proteins. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...
s in solution, though they are largely
alpha helical The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
in membranes; however, at sufficiently high concentration, they undergo a dramatic
conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
to form a
beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a g ...
-rich
tertiary structure Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may int ...
that aggregates to form
amyloid fibril Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the h ...
s. These fibrils and
oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
ic forms of Aβ deposit outside neurons in formations known as
senile plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of micr ...
. There are different types of plaques, including the ''diffuse'', ''compact'', ''cored'' or
neuritic plaque Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of mi ...
types, as well as Aβ deposits in the walls of small blood vessel walls in the brain called
cerebral amyloid angiopathy Cerebral amyloid angiopathy (CAA) is a form of angiopathy in which amyloid beta peptide deposits in the walls of small to medium blood vessels of the central nervous system and meninges. The term ''congophilic'' is sometimes used because the pre ...
. AD is also considered a
tauopathy Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known a ...
due to abnormal aggregation of the
tau protein The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintaining ...
, a
microtubule-associated protein In cell biology, microtubule-associated proteins (MAPs) are proteins that interact with the microtubules of the cellular cytoskeleton. MAPs are integral to: the stability of the cell and its internal structures and the transport of components within ...
expressed in neurons that normally acts to stabilize
microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 an ...
in the cell
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
. Like most microtubule-associated proteins, tau is normally regulated by
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
; however, in Alzheimer's disease, hyperphosphorylated tau accumulates as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as
neurofibrillary tangles Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is k ...
and as dystrophic
neurite A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture ...
s associated with amyloid plaques. Although little is known about the process of filament assembly, depletion of a
prolyl isomerase Prolyl isomerase (also known as peptidylprolyl isomerase or PPIase) is an enzyme () found in both prokaryotes and eukaryotes that interconverts the ''cis'' and ''trans'' isomers of peptide bonds with the amino acid proline. Proline has an unusua ...
protein in the
parvulin ] Parvulin, a 92-amino acid protein discovered in E. coli in 1994,Rahfeld JU, Schierhorn A, Mann KH. (1994). A novel peptidyl-prolyl cis/trans isomerase from Escherichia coli. ''FEBS Lett'' 343:65. is the smallest known protein with prolyl isomera ...
family has been shown to accelerate the accumulation of abnormal tau. Neuroinflammation is also involved in the complex cascade leading to AD pathology and symptoms. Considerable pathological and clinical evidence documents immunological changes associated with AD, including increased pro-inflammatory cytokine concentrations in the blood and cerebrospinal fluid. Whether these changes may be a cause or consequence of AD remains to be fully understood, but inflammation within the brain, including increased reactivity of the resident
microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
towards amyloid deposits, has been implicated in the pathogenesis and progression of AD. Much of the known biochemistry of Alzheimer's disease has been deciphered through research using
experimental models of Alzheimer's disease Experimental models of Alzheimer's disease are organism or cellular models used in research to investigate biological questions about Alzheimer's disease as well as develop and test novel therapeutic treatments. Alzheimer's disease is a progressive ...
.


Neuropathology

At a
macroscopic The macroscopic scale is the length scale on which objects or phenomena are large enough to be visible with the naked eye, without magnifying optical instruments. It is the opposite of microscopic. Overview When applied to physical phenomena an ...
level, AD is characterized by loss of
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s and
synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
s in the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...
and certain subcortical regions. This results in gross
atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...
of the affected regions, including degeneration in the
temporal lobe The temporal lobe is one of the four Lobes of the brain, major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe ...
and
parietal lobe The parietal lobe is one of the four major lobes of the cerebral cortex in the brain of mammals. The parietal lobe is positioned above the temporal lobe and behind the frontal lobe and central sulcus. The parietal lobe integrates sensory informa ...
, and parts of the
frontal cortex The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove betwe ...
and
cingulate gyrus The cingulate cortex is a part of the brain situated in the medial aspect of the cerebral cortex. The cingulate cortex includes the entire cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the ci ...
. Both
amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of micr ...
and
neurofibrillary tangle Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is kn ...
s are clearly visible by
microscopy Microscopy is the technical field of using microscopes to view objects and areas of objects that cannot be seen with the naked eye (objects that are not within the resolution range of the normal eye). There are three well-known branches of micr ...
in AD brains. Plaques are dense, mostly
insoluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubil ...
deposits of
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
and
cellular Cellular may refer to: *Cellular automaton, a model in discrete mathematics * Cell biology, the evaluation of cells work and more * ''Cellular'' (film), a 2004 movie *Cellular frequencies, assigned to networks operating in cellular RF bands *Cell ...
material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.


Biochemical characteristics

Fundamental to the understanding of Alzheimer's disease is the biochemical events that leads to accumulation of the amyloid-beta plaques and tau-protein tangles. A delicate balance of the enzymes
secretase Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane. 300px, Processing of the amyloid-beta precursor protein Among other roles in the cell, secretases act on the amyloid-beta precursor protein (APP) ...
s regulate the amyloid-beta accumulation. Alpha Secretase can render a non-pathological (non-amyloidogenic) Amyloid Beta (DOI: 10.2174/156720512799361655). Recently, a link between cholinergic neuronal activity and the activity of alpha-secretase has been highlighted, which can discourage Amyloid-beta proteins deposition in brain of patients with Alzheimer's disease. Alzheimer's disease has been identified as a
protein misfolding In medicine, proteinopathy (; 'pref''. protein -pathy 'suff''. disease proteinopathies ''pl''.; proteinopathic ''adj''), or proteopathy, protein conformational disorder, or protein misfolding disease refers to a class of diseases in which certa ...
disease, or
proteopathy In medicine, proteinopathy (; 'pref''. protein -pathy 'suff''. disease proteinopathies ''pl''.; proteinopathic ''adj''), or proteopathy, protein conformational disorder, or protein misfolding disease refers to a class of diseases in which certa ...
, due to the accumulation of abnormally folded Amyloid-beta proteins in the brains of AD patients. Abnormal amyloid-beta accumulation can first be detected using cerebrospinal fluid analysis and later using positron emission tomography (PET). Although AD shares pathophysiological mechanisms with prion diseases, it is not transmissible like prion diseases. Amyloid-beta, also written Aβ, is a short
peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...
that is a
proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
byproduct of the
transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator ...
(APP), whose function is unclear but thought to be involved in neuronal development. The
presenilin Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset ...
s are components of a proteolytic complex involved in APP processing and degradation. Although amyloid beta
monomer In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification Mo ...
s are harmless, they undergo a dramatic
conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
at sufficiently high concentration to form a
beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a g ...
-rich
tertiary structure Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may int ...
that aggregates to form
amyloid fibrils Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...
that deposit outside neurons in dense formations known as ''senile plaques'' or ''neuritic plaques'', in less dense aggregates as ''diffuse plaques'', and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or congophilic angiopathy. AD is also considered a
tauopathy Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known a ...
due to abnormal aggregation of the
tau protein The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintaining ...
, a
microtubule-associated protein In cell biology, microtubule-associated proteins (MAPs) are proteins that interact with the microtubules of the cellular cytoskeleton. MAPs are integral to: the stability of the cell and its internal structures and the transport of components within ...
expressed in neurons that normally acts to stabilize
microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 an ...
in the cell
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
. Like most microtubule-associated proteins, tau is normally regulated by
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
; however, in AD patients, hyperphosphorylated tau accumulates as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as ''neurofibrillary tangles'' and as dystrophic
neurite A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture ...
s associated with amyloid plaques. Levels of the neurotransmitter
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
(ACh) are reduced. Levels of other neurotransmitters
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
,
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
, and
somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...
are also often reduced. Replenishing the ACh by anti-cholinesterases is an approved mode of treatment by FDA. An alternative method of stimulating ACh receptors of M1-M3 types by synthetic agonists that have a slower rate of dissociation from the receptor has been proposed as next generation cholinomimetic in Alzheimer's disease 5/sup>.


Potential disease mechanisms

While the gross histological features of AD in the brain have been well characterized, several different hypotheses have been advanced regarding the primary cause. Among the oldest hypotheses is the
cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation. F ...
hypothesis, which suggests that deficiency in cholinergic signaling initiates the progression of the disease. Other hypotheses suggest that either misfolding tau protein inside the cell or aggregation of amyloid beta outside the cell initiates the cascade leading to AD pathology. Still other hypotheses propose metabolic factors, vascular disturbance, or chronically elevated inflammation in the brain as the primary cause for AD. While researchers have not identified a clear causative pathway originating from any of the molecular hypothesis that explains the gross anatomical changes observed in advanced AD, variants of the amyloid beta hypothesis of molecular initiation have become dominant among many researchers to date


Cholinergic hypothesis

The cholinergic hypothesis of AD development was first proposed in 1976 by Peter Davies and A.J.F Maloney. It states that Alzheimer's begins as a deficiency in the production of
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
, a vital
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
. Much early therapeutic research was based on this hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based on this hypothesis and work to preserve acetylcholine by inhibiting
acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme Enzymes () are proteins that a ...
s (enzymes that break down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and other research have led to the conclusion that acetylcholine deficiencies may not be directly causal, but are a result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be impractical. More recent hypotheses center on the effects of the misfolded and aggregated proteins, amyloid beta and tau. The two positions are lightheartedly described as "ba-ptist" and "tau-ist" viewpoints in one scientific publication. Therein, it is suggested that "Tau-ists" believe that the
tau protein The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintaining ...
abnormalities initiate the disease cascade, while "ba-ptists" believe that
beta amyloid Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labio ...
deposits are the causative factor in the disease.


Tau hypothesis

The hypothesis that tau is the primary causative factor has long been grounded in the observation that deposition of amyloid plaques does not correlate well with neuron loss. A mechanism for neurotoxicity has been proposed based on the loss of microtubule-stabilizing tau protein that leads to the degradation of the cytoskeleton. However, consensus has not been reached on whether tau hyperphosphorylation precedes or is caused by the formation of the abnormal helical filament aggregates. Support for the tau hypothesis also derives from the existence of other diseases known as
tauopathies Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known ...
in which the same protein is identifiably misfolded. However, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.


Amyloid hypothesis

The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on
chromosome 21 Chromosome 21 is one of the 23 pairs of chromosomes in humans. Chromosome 21 is both the smallest human autosome and chromosome, with 48 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cells. ...
, and patients with
trisomy 21 A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes). Description and causes Most organisms that reprodu ...
– better known as
Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
– who have an extra gene copy exhibit AD-like disorders by 40 years of age. The amyloid hypothesis points to the
cytotoxicity Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...
of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. This hypothesis is supported by the observation that higher levels of a variant of the beta amyloid protein known to form fibrils faster ''in vitro'' correlate with earlier onset and greater cognitive impairment in mouse models and with AD diagnosis in humans. However, mechanisms for the induced calcium influx, or proposals for alternative cytotoxic mechanisms, by mature fibrils are not obvious. A more recent variation of the amyloid hypothesis identifies the cytotoxic species as an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an
oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
ic species, possibly toroidal or star-shaped with a central channel that may induce apoptosis by physically piercing the cell membrane. This ion channel hypothesis postulates that oligomers of soluble, non-fibrillar Aβ form membrane ion channels allowing unregulated calcium influx into neurons. A related alternative suggests that a globular oligomer localized to dendritic processes and
axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
s in neurons is the cytotoxic species. The prefibrillar aggregates were shown to be able to disrupt the membrane. The cytotoxic-fibril hypothesis presents a clear target for drug development: inhibit the fibrillization process. Much early development work on
lead compound A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, b ...
s has focused on this inhibition; most are also reported to reduce neurotoxicity, but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta. For example,
apomorphine Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antagon ...
was seen to significantly improve memory function through the increased successful completion of the
Morris Water Maze The Morris water navigation task, also known as the Morris water maze (not to be confused with ''Water maze (neuroscience), water maze''), is a behavioral procedure mostly used with rodents. It is widely used in behavioral neuroscience to study ...
. ;Soluble intracellular (o)Aβ42 Two papers have shown that oligomeric (o)Aβ42 (a species of Aβ), in soluble intracellular form, acutely inhibits
synaptic transmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
, a pathophysiology that characterizes AD (in its early stages), by activating
casein kinase 2 Casein kinase 2 ()(CK2/CSNK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. De-regulation of CK2 has been linked to tumor ...
.


Inflammatory hypothesis

Converging evidence suggests/supports that a sustained inflammatory response in the brain is a core feature of AD pathology and may be a key factor in AD pathogenesis. The brains of AD patients exhibit several markers of increased inflammatory signaling. The inflammatory hypothesis proposes that chronically elevated inflammation in the brain is a crucial component to the amyloid cascade in the early phases of AD and magnifies disease severity in later stages of AD. Aβ is present in healthy brains and serves a vital physiological function in recovery from neuronal injury, protection from infection, and repair of the blood-brain barrier, however it is unknown how Aβ production starts to exceed the clearance capacity of the brain and initiates AD progression. A possible explanation is that Aβ causes
microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
, the resident immune cell of the brain, to become activated and secrete pro-inflammatory signaling molecules, called
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s, which recruit other local microglia. While acute microglial activation, as in response to injury, is beneficial and allows microglia to clear Aβ and other cellular debris via phagocytosis, chronically activated microglia exhibit decreased efficiency in Aβ clearance. Despite this reduced AB clearance capacity, activated microglia continue to secrete pro-inflammatory cytokines like interleukins 1β and 6 (IL-6, IL-1β) and tumor necrosis factor-alpha (TNF-a), as well as reactive oxygen species which disrupt healthy synaptic functioning and eventually cause neuronal death. The loss of synaptic functioning and later neuronal death is responsible for the cognitive impairments and loss of volume in key brain regions which are associated with AD. IL-1B, IL-6, and TNF-a cause further production of Aβ oligomers, as well as tau hyperphosphorylation, leading to continued microglia activation and creating a feed forward mechanism in which Aβ production is increased and Aβ clearance is decreased eventually causing the formation of Aβ plaques.


Cholesterol hypothesis

The cholesterol hypothesis is a combination of the amyloid hypothesis, tau hypothesis, and potentially the inflammatory hypothesis. Cholesterol was shown to be upstream of both amyloid and tau production. The cholesterol is produced in the astrocytes and shipped to neurons where it activates amyloid production through a process called
substrate presentation Substrate presentation is a biological process that activates a protein. The protein is sequestered away from its substrate and then activated by release and exposure of the protein to its substrate. A substrate is typically the substance on which ...
. The process required apoE. Cholesterol's regulation of Tau production is less well understood, but knocking out the cholesterol synthesis enzyme SREBP2 decreased Tau phosphorylation. Innate immunity triggers cholesterol synthesis and cells take up the cholesterol. Presumably a cell in the brain dies with old age and this triggers innate immunity. More studies are needed to directly tie the inflammatory hypothesis to cholesterol synthesis in the brain.


Reelin hypothesis

A relatively recent hypothesis based mainly on rodent experiments links the onset of Alzheimer's disease to the hypofunction of the large extracellular protein
reelin Reelin, encoded by the ''RELN'' gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this import ...
. A decrease of reelin in the human entorhinal cortex where the disease typically initiates is evident while compensatory increase of reelin levels in other brain structures of the patients is also reported. Of key importance, overexpression of reelin rescues the cognitive capacities of Alzheimer's disease model mice and τ-protein overexpressing mice. A recent circuit level model proposed a mechanism of how reelin depletion leads to the early deterioration of
episodic memory Episodic memory is the memory of everyday events (such as times, location geography, associated emotions, and other contextual information) that can be explicitly stated or conjured. It is the collection of past personal experiences that occurred ...
thereby laying the theoretical foundation of the reelin hypothesis.


Isoprenoid changes

A 1994 study showed that the
isoprenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes", ...
changes in Alzheimer's disease differ from those occurring during normal aging and that this disease cannot, therefore, be regarded as a result of
premature aging Progeroid syndromes (PS) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. The term ''progeroid syndrome'' does not necessarily imply progeria (Hutchinson–Gilford ...
. During aging the
human brain The human brain is the central organ of the human nervous system, and with the spinal cord makes up the central nervous system. The brain consists of the cerebrum, the brainstem and the cerebellum. It controls most of the activities of the ...
shows a progressive increase in levels of
dolichol Dolichol refers to any of a group of long-chain mostly unsaturated organic compounds that are made up of varying numbers of isoprene units terminating in an α-saturated isoprenoid group, containing an alcohol functional group. Functions Dolich ...
, a reduction in levels of
ubiquinone Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-benzoq ...
, but relatively unchanged concentrations of
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
and dolichyl phosphate. In Alzheimer's disease, the situation is reversed with decreased levels of
dolichol Dolichol refers to any of a group of long-chain mostly unsaturated organic compounds that are made up of varying numbers of isoprene units terminating in an α-saturated isoprenoid group, containing an alcohol functional group. Functions Dolich ...
and increased levels of
ubiquinone Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-benzoq ...
. The concentrations of dolichyl phosphate are also increased, while
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
remains unchanged. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of
glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not al ...
in the diseased brain and the increase in the endogenous
anti-oxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants, ...
ubiquinone Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-benzoq ...
an attempt to protect the brain from
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
, for instance induced by
lipid peroxidation Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which radical (chemistry), free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by ...
. Ropren, identified previously in Russia, is neuroprotective in a rat model of Alzheimer's disease.


Glucose consumption

The human brain is one of the most metabolically active organs in the body and metabolizes a large amount of glucose to produce cellular energy in the form of
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
(ATP). Despite its high energy demands, the brain is relatively inflexible in its ability to utilize substrates for energy production and relies almost entirely on circulating glucose for its energy needs. This dependence on glucose puts the brain at risk if the supply of glucose is interrupted, or if its ability to metabolize glucose becomes defective. If the brain is not able to produce ATP, synapses cannot be maintained and cells cannot function, ultimately leading to impaired cognition. Imaging studies have shown decreased utilization of glucose in the brains of Alzheimer's disease patients early in the disease, before clinical signs of cognitive impairment occur. This decrease in
glucose metabolism Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms. Carbohydrates are central to many essential metabolic pathways. Plants ...
worsens as clinical symptoms develop and the disease progresses. Studies have found a 17%-24% decline in cerebral glucose metabolism in patients with Alzheimer's disease, compared with age-matched controls. Numerous imaging studies have since confirmed this observation. Abnormally low rates of cerebral glucose metabolism are found in a characteristic pattern in the Alzheimer's disease brain, particularly in the posterior cingulate, parietal, temporal, and prefrontal cortices. These brain regions are believed to control multiple aspects of
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...
and
cognition Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
. This metabolic pattern is reproducible and has even been proposed as a diagnostic tool for Alzheimer's disease. Moreover, diminished cerebral glucose metabolism (DCGM) correlates with plaque density and cognitive deficits in patients with more advanced disease. Diminished cerebral glucose metabolism (DCGM) may not be solely an artifact of brain cell loss since it occurs in asymptomatic patients at risk for Alzheimer's disease, such as patients homozygous for the epsilon 4 variant of the
apolipoprotein E Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease. APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
gene (APOE4, a genetic risk factor for Alzheimer's disease), as well as in inherited forms of Alzheimer's disease. Given that DCGM occurs before other clinical and pathological changes occur, it is unlikely to be due to the gross cell loss observed in Alzheimer's disease. In imaging studies involving young adult APOE4 carriers, where there were no signs of cognitive impairment, diminished cerebral glucose metabolism (DCGM) was detected in the same areas of the brain as older subjects with Alzheimer's disease. However, DCGM is not exclusive to APOE4 carriers. By the time Alzheimer's has been diagnosed, DCGM occurs in genotypes APOE3/E4, APOE3/E3, and APOE4/E4. Thus, DCGM is a metabolic
biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
for the disease state.


Insulin signaling

A connection has been established between Alzheimer's disease and diabetes during the past decade, as
insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
, which is a characteristic hallmark of
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, has also been observed in brains of subjects with Alzheimer's disease. Neurotoxic oligomeric
amyloid-β Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...
species decrease the expression of insulin receptors on the neuronal cell surface and abolish neuronal insulin signaling. It has been suggested that neuronal
ganglioside A ganglioside is a molecule composed of a glycosphingolipid (ceramide and oligosaccharide) with one or more sialic acids (e.g. ''N''-acetylneuraminic acid, NANA) linked on the sugar chain. NeuNAc, an acetylated derivative of the carbohydrate sia ...
s, which take part in the formation of membrane
lipid microdomain Lipid microdomains are formed when lipids undergo lateral phase separations yielding stable coexisting lamellar domains. These phase separations can be induced by changes in temperature, pressure, ionic strength or by the addition of divalent cat ...
s, facilitate amyloid-β-induced removal of the insulin receptors from the neuronal surface. In Alzheimer's disease, oligomeric amyloid-β species trigger
TNF-α Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
signaling. c-Jun N-terminal kinase activation by TNF-α in turn activates stress-related kinases and results in IRS-1 serine phosphorylation, which subsequently blocks downstream insulin signaling. The resulting insulin resistance contributes to cognitive impairment. Consequently, increasing neuronal insulin sensitivity and signaling may constitute a novel therapeutic approach to treat Alzheimer's disease.


Oxidative stress

Oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
is emerging as a key factor in the
pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...
of AD.
Reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...
(ROS) over-production is thought to play a critical role in the accumulation and deposition of
amyloid beta Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...
in AD. Brains of AD patients have elevated levels of oxidative DNA damage in both
nuclear Nuclear may refer to: Physics Relating to the nucleus of the atom: * Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics *Nuclear space *Nuclear ...
and
mitochondrial DNA Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...
, but the mitochondrial DNA has approximately 10-fold higher levels than nuclear DNA. Aged mitochondria may be the critical factor in the origin of
neurodegeneration A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
in AD. Even individuals with
mild cognitive impairment Mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected based on an individual's age and education but which are not significant enough to interfere with instrumental activities of ...
, the phase between normal aging and early dementia, have increased oxidative damage in their nuclear and mitochondrial brain DNA (see
Aging brain Aging is a major risk factor for most common neurodegenerative diseases, including mild cognitive impairment, dementias including Alzheimer's disease, cerebrovascular disease, Parkinson's disease, and Lou Gehrig's disease. While much research has f ...
).


Large gene instability hypothesis

A bioinformatics analysis in 2017 revealed that extremely large human genes are significantly over-expressed in brain and take part in the postsynaptic architecture. These genes are also highly enriched in cell adhesion Gene Ontology (GO) terms and often map to chromosomal fragile sites. The majority of known Alzheimer's disease risk gene products including the amyloid precursor protein (APP) and gamma-secretase, as well as the APOE receptors and GWAS risk loci take part in similar cell adhesion mechanisms. It was concluded that dysfunction of cell and synaptic adhesion is central to Alzheimer's disease pathogenesis, and mutational instability of large synaptic adhesion genes may be the etiological trigger of neurotransmission disruption and synaptic loss in brain aging. As a typical example, this hypothesis explains the APOE risk locus of AD in context of signaling of its giant lipoprotein receptor, LRP1b which is a large tumor-suppressor gene with brain-specific expression and also maps to an unstable chromosomal fragile site. The large gene instability hypothesis puts the DNA damage mechanism at the center of Alzheimer's disease pathophysiology.


DNA damage

Naturally occurring DNA double-strand breaks (DSBs) arise in human cells largely from single-strand breaks induced by various processes including the activity of reactive oxygen species, topoisomerases, and hydrolysis due to thermal fluctuations. In neurons DSBs are induced by a type II topoisomerase as part of the physiologic process of memory formation. DSBs are present in both neurons and astrocytes in the postmortem human
hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
of AD patients at a higher level than in non-AD individuals. AD is associated with an accumulation of DSBs in neurons and astrocytes in the hippocampus and frontal cortex from early stages onward. DSBs are increased in the vicinity of amyloid plaques in the hippocampus, indicating a potential role for Aβ in DSB accumulation or vice versa. The predominant mechanism for repairing DNA double-strand breaks is non-homologous end joining (NHEJ), a mechanism that utilizes the DNA-dependent protein kinase (DNA-PK) complex. The end joining activity and protein levels of DNA-PK catalytic subunit are significantly lower in AD brains than in normal brains.


References

{{DEFAULTSORT:Biochemistry Of Alzheimer's Disease Alzheimer's disease Neurology Unsolved problems in neuroscience Pathology