Amyloid beta (Aβ or Abeta) denotes
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.
...
s of 36–43
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
s 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
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), which is cleaved by
beta secretase
Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enco ...
and
gamma secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. Th ...
to yield Aβ in a cholesterol-dependent process and
substrate presentation. Aβ molecules can aggregate to form flexible soluble
oligomers which may exist in several forms. It is now believed that certain misfolded oligomers (known as "seeds") can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a
prion infection. The oligomers are toxic to
nerve cell
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. No ...
s. The other protein implicated in Alzheimer's disease,
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 ...
, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.
A study has suggested that APP and its amyloid potential is of ancient origins, dating as far back as early
deuterostomes
Deuterostomia (; in Greek) are animals typically characterized by their anus forming before their mouth during embryonic development. The group's sister clade is Protostomia, animals whose digestive tract development is more varied. Some exampl ...
.
Normal function
The normal function of Aβ is not well understood.
Though some animal studies have shown that the absence of Aβ does not lead to any obvious loss of physiological function,
several potential activities have been discovered for Aβ, including activation of
kinase enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s,
protection against
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
,
regulation 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 ...
transport,
functioning as a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
,
and anti-microbial activity (potentially associated with Aβ's pro-
inflammatory activity).
The
glymphatic system
The glymphatic system (or glymphatic clearance pathway, or paravascular system) was described and named in 2013 as a system for waste clearance in the central nervous system (CNS) of vertebrates. According to this model, cerebrospinal fluid (CSF) ...
clears metabolic waste from the mammalian brain, and in particular amyloid beta.
Indeed, a number of proteases have been implicated by both genetic and biochemical studies as being responsible for the recognition and degradation of amyloid beta; these include insulin degrading enzyme. and presequence protease The rate of removal is significantly increased during sleep. However, the significance of the lymphatic system in Aβ clearance in Alzheimer's disease is unknown.
Disease associations
Aβ is the main component of
amyloid 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 ...
s, extracellular deposits found 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 ve ...
s of people with Alzheimer's disease. Aβ can also form the deposits that line
cerebral blood vessel
Cerebral circulation is the movement of blood through a network of cerebral arteries and veins supplying the brain. The rate of cerebral blood flow in an adult human is typically 750 milliliters per minute, or about 15% of cardiac output. Arter ...
s in
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 ...
. The plaques are composed of a tangle of Aβ
oligomers
and regularly ordered aggregates called
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 ...
, a
protein fold
A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similari ...
shared by other peptides such as the
prions associated with protein misfolding diseases.
Alzheimer's disease
Research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer's disease.
It is generally believed that Aβ oligomers are the most toxic.
The
ion channel hypothesis postulates that oligomers of soluble, non-fibrillar Aβ form membrane
ion channels allowing the unregulated
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
influx into neurons that underlies disrupted calcium ion
homeostasis
In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
and
apoptosis seen in Alzheimer's disease. Computational studies have demonstrated that also Aβ peptides embedded into the membrane as monomers with predominant helical configuration, can oligomerize and eventually form channels whose stability and conformation are sensitively correlated to the concomitant presence and arrangement of cholesterol. A number of genetic, cell biology, biochemical and animal studies using
experimental models support the concept that Aβ plays a central role in the development of Alzheimer's disease pathology.
Brain Aβ is elevated in people with sporadic Alzheimer's disease. Aβ is the main constituent of brain
parenchymal
Parenchyma () is the bulk of functional substance in an animal organ or structure such as a tumour. In zoology it is the name for the tissue that fills the interior of flatworms.
Etymology
The term ''parenchyma'' is New Latin from the word ...
and vascular amyloid; it contributes to cerebrovascular lesions and is neurotoxic.
It is unresolved how Aβ accumulates in the central nervous system and subsequently initiates the disease of cells. Some researchers have found that the Aβ oligomers induce some of the symptoms of Alzheimer's disease by competing with insulin for binding sites on the insulin receptor, thus impairing glucose metabolism in the brain.
Significant efforts have been focused on the mechanisms responsible for Aβ production, including the proteolytic enzymes gamma- and β-secretases which generate Aβ from its precursor protein, APP (amyloid precursor protein).
Aβ circulates in plasma, cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) mainly as soluble Aβ40
Amyloid plaques contain both Aβ40 and Aβ42,
while vascular amyloid is predominantly the shorter Aβ40. Several sequences of Aβ were found in both lesions.
Generation of Aβ in the central nervous system may take place in the neuronal axonal membranes after APP-mediated axonal transport of β-secretase and presenilin-1.
Increases in either total Aβ levels or the relative concentration of both Aβ40 and Aβ42 (where the former is more concentrated in cerebrovascular plaques and the latter in
neuritic plaques)
have been implicated 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 both familial and sporadic Alzheimer's disease. Due to its more hydrophobic nature, the Aβ42 is the most amyloidogenic form of the peptide. However the central sequence KLVFFAE is known to form amyloid on its own, and probably forms the core of the fibril. One study further correlated Aβ42 levels in the brain not only with onset of Alzheimer's disease, but also reduced cerebrospinal fluid pressure, suggesting that a build-up or inability to clear Aβ42 fragments may play a role into the pathology.
The "
amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is not conclusively established. An alternative hypothesis is that amyloid
oligomers rather than plaques are responsible for the disease.
Mice that are genetically engineered to express oligomers but not plaques (APP
E693Q) develop the disease. Furthermore, mice that are in addition engineered to convert oligomers into plaques (APP
E693Q X
PS1ΔE9), are no more impaired than the oligomer only mice.
Intra-cellular deposits of
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 ...
are also seen in the disease, and may also be implicated, as has aggregation of
alpha synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.
It is abundant in the brain, while smaller a ...
.
Cancer
While Aβ has been implicated in
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
development, prompting studies on a variety of cancers to elucidate the nature of its possible effects, results are largely inconclusive. Aβ levels have been assessed in relation to a number of cancers, including
esophageal,
colorectal
The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...
,
lung, and
hepatic
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it is ...
, in response to observed reductions in risk for developing Alzheimer's disease in survivors of these cancers. All cancers were shown to be associated positively with increased Aβ levels, particularly hepatic cancers. This direction of association however has not yet been established. Studies focusing on human breast cancer cell lines have further demonstrated that these cancerous cells display an increased level of expression of amyloid precursor protein.
Down syndrome
Adults with
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 ...
had accumulation of amyloid in association with evidence of Alzheimer's disease, including declines in cognitive functioning, memory, fine motor movements, executive functioning, and visuospatial skills.
Formation
Aβ is formed after sequential
cleavage of the
amyloid 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), a
transmembrane
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 frequent ...
glycoprotein of undetermined function. APP can be cleaved by the
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 protease ...
enzymes
α-,
β- and
γ-secretase; Aβ protein is generated by successive action of the β and γ secretases. The γ secretase, which produces the
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 30-51
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
residues in length.
The most common isoforms are Aβ
40 and Aβ
42; the longer form is typically produced by cleavage that occurs in the
endoplasmic reticulum, while the shorter form is produced by cleavage in the trans-
Golgi network.
Genetics
Autosomal-dominant mutations in APP cause
hereditary early-onset Alzheimer's disease
Early-onset Alzheimer's disease, also called younger-onset Alzheimer's, is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive ...
(familial AD, fAD). This form of AD accounts for no more than 10% of all cases, and the vast majority of AD is not accompanied by such mutations.
However, familial Alzheimer's disease is likely to result from altered
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 protease ...
processing. This is evidenced by the fact that many mutations that lead to fAD occur near γ-secretase cleavage sites on APP. One of the most common mutations causing fAD,
London Mutation, occurs at codon 717 of the APP gene, and results in a valine to isoleucine amino acid substitution. Histochemical analysis of the APP V717I mutation has revealed extensive Aβ pathology throughout neuroaxis as well as widespread
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 ...
(CAA).
The gene for the amyloid precursor protein 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. M ...
, and accordingly people with
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 ...
have a very high incidence of Alzheimer's disease.
Structure and toxicity
Amyloid beta is commonly thought to be
intrinsically unstructured, meaning that in solution it does not acquire a unique tertiary
fold but rather populates a set of structures. As such, it cannot be crystallized and most structural knowledge on amyloid beta comes from
NMR
Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with ...
and
molecular dynamics
Molecular dynamics (MD) is a computer simulation method for analyzing the physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the dynamic "evolution" of t ...
. Early NMR-derived models of a 26-aminoacid polypeptide from amyloid beta (Aβ 10–35) show a collapsed
coil structure devoid of significant
secondary structure content.
However, the most recent (2012) NMR structure of (Aβ 1-40) has significant secondary and tertiary structure.
Replica exchange
Parallel tempering in physics and statistics, is a computer simulation method typically used to find the lowest free energy state of a system of many interacting particles at low temperature. That is, the one expected to be observed in reality. ...
molecular dynamics studies suggested that amyloid beta can indeed populate multiple discrete structural states;
more recent studies identified a multiplicity of discrete conformational clusters by statistical analysis.
By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states,
with the C-terminus of amyloid beta 1-42 being more structured than that of the 1-40 fragment.
Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure.
In contrast, soluble oligomers prepared in the presence of detergents seem to feature substantial beta sheet content with mixed parallel and antiparallel character, different from fibrils;
computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.
The suggested mechanisms by which amyloid beta may damage and cause neuronal death include the generation of
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 ...
during the process of its self-aggregation. When this occurs on the membrane of neurons in vitro, it causes
lipid peroxidation and the generation of a toxic aldehyde called
4-hydroxynonenal
4-Hydroxynonenal, or 4-hydroxy-2-nonenal or 4-HNE or HNE, (), is an α,β-unsaturated hydroxyalkenal that is produced by lipid peroxidation in cells. 4-HNE is the primary α,β-unsaturated hydroxyalkenal formed in this process. It is a colorless ...
which, in turn, impairs the function of ion-motive ATPases,
glucose transporters and
glutamate transporters. As a result, amyloid beta promotes depolarization of the synaptic membrane, excessive calcium influx and mitochondrial impairment.
Aggregations of the amyloid-beta peptide disrupt membranes in vitro.
In AD brains, in addition to the characteristic aggregation of Aβ peptides that causes amyloid (senile) plaques,
DNA damages also accumulate.
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 ...
may be the major source of DNA damage in AD brains.
CDK5
Cyclin-dependent kinase 5 is a protein, and more specifically an enzyme, that is encoded by the Cdk5 gene. It was discovered 15 years ago, and it is saliently expressed in post-mitotic central nervous system neurons (CNS).
The molecule belongs ...
kinase phosphorylates APP at threonine 568 which stimulates Aβ peptide accumulation, and CDK5 activities also affect the DNA damage response, supporting the concept of a linkage of DNA damage with AD.
Intervention strategies
Researchers in Alzheimer's disease have identified several strategies as possible interventions against amyloid:
*
β-Secretase inhibitors. These work to block the first cleavage of APP inside of the cell, at the endoplasmic reticulum.
*
γ-Secretase inhibitors (e. g.
semagacestat
Semagacestat (LY-450139) was a candidate drug for a causal therapy against Alzheimer's disease. It was originally developed by Eli Lilly and Elan, and clinical trials were conducted by Eli Lilly. Phase III trials included over 3000 patients, but ...
). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aβ and its toxic fragments.
* Selective Aβ
42 lowering agents (e. g.
tarenflurbil). These modulate γ-secretase to reduce Aβ
42 production in favor of other (shorter) Aβ versions.
β- and γ-secretase are responsible for the generation of Aβ from the release of the intracellular domain of APP, meaning that compounds that can partially inhibit the activity of either β- or γ-secretase are highly sought after. In order to initiate partial inhibition of β- and γ-secretase, a compound is needed that can block the large active site of aspartyl proteases while still being capable of bypassing the blood-brain barrier. To date, human testing has been avoided due to concern that it might interfere with signaling via Notch proteins and other cell surface receptors.
*
Immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
. This stimulates the host immune system to recognize and attack Aβ, or provide antibodies that either prevent plaque deposition or enhance clearance of plaques or Aβ oligomers. Oligomerization is a chemical process that converts individual molecules into a chain consisting of a finite number of molecules. Prevention of oligomerization of Aβ has been exemplified by active or passive Aβ immunization. In this process antibodies to Aβ are used to decrease cerebral plaque levels. This is accomplished by promoting microglial clearance and/or redistributing the peptide from the brain to systemic circulation. Antibodies that target Aβ and are currently in clinical trials included
aducanumab,
bapineuzumab,
crenezumab,
gantenerumab,
lecanemab, and
solanezumab.
Amyloid beta vaccines that are currently in clinical trials include
CAD106 and
UB-311.
However literature reviews have raised questions as to immunotherapy's overall efficacy. One such study assessing ten anti-Ab42 antibodies showed minimal cognitive protection and results within each trial, as symptoms were too far progressed by the time of application to be useful. Further development is still required for application to those who are presymptomatic to assess their effectiveness early into disease progression.
* Anti-aggregation agents
such as
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 antag ...
, or
carbenoxolone
Carbenoxolone (CBX) is a glycyrrhetinic acid derivative with a steroid-like structure, similar to substances found in the root of the licorice plant. Carbenoxolone is used for the treatment of peptic, esophageal and oral ulceration and inflammat ...
. The latter has commonly been used as a treatment for peptic ulcers, but also displays neuroprotective properties, shown to improve cognitive functions such as verbal fluency and memory consolidation. By binding with high affinity to Aβ42 fragments, primarily via hydrogen bonding, carbenoxolone captures the peptides before they can aggregate together, rendering them inert, as well as destabilizes those aggregates already formed, helping to clear them.
This is a common mechanism of action of anti-aggregation agents at large.
* Studies comparing synthetic to recombinant Aβ
42 in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant Aβ
42 had a faster fibrillation rate and greater toxicity than synthetic amyloid beta 1-42 peptide.
* Modulating cholesterol homeostasis has yielded results that show that chronic use of cholesterol-lowering drugs, such as the statins, is associated with a lower incidence of AD. In APP genetically modified mice, cholesterol-lowering drugs have been shown to reduce overall pathology. While the mechanism is poorly understood it appears that cholesterol-lowering drugs have a direct effect on APP processing.
*
Memantine
Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth.
Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots ...
is an Alzheimer's disease drug which has received widespread approval. It is a non-competitive N-methyl-D-aspartate (
NMDA
''N''-methyl--aspartic acid or ''N''-methyl--aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike ...
) channel blocker. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. It is an option for the management of those with moderate to severe Alzheimer's disease (modest effect). The study showed that 20 mg/day improved cognition, functional ability and behavioural symptoms.
Measuring amyloid beta
Imaging compounds, notably
Pittsburgh compound B
Pittsburgh compound B (PiB) is a radioactive analog of thioflavin T, which can be used in positron emission tomography scans to image beta-amyloid plaques in neuronal tissue. Due to this property, Pittsburgh compound B may be used in investiga ...
, (6-OH-BTA-1, a
thioflavin), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with
PET
A pet, or companion animal, is an animal kept primarily for a person's company or entertainment rather than as a working animal, livestock, or a laboratory animal. Popular pets are often considered to have attractive appearances, intelligence ...
imaging, is used to image areas of plaque deposits in those with Alzheimer's.
Post mortem or in tissue biopsies
Amyloid beta can be measured semiquantitatively with
immunostaining, which also allows one to determine location. Amyloid beta may be primarily vascular, as in
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 ...
, or in
amyloid plaques in
white matter
White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...
.
One sensitive method is
ELISA
The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presen ...
which is an immunosorbent assay which utilizes a pair of
antibodies that recognize amyloid beta.
Atomic force microscopy, which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of amyloid beta in vitro.
Vibrational microspectroscopy is a label-free method that measures the vibration of molecules in tissue samples.
Amyloid proteins like Aβ can be detected with this technique because of their high content of β-sheet structures.
Recently, the formation of Aβ fibrils was resolved in different
plaque
Plaque may refer to:
Commemorations or awards
* Commemorative plaque, a plate or tablet fixed to a wall to mark an event, person, etc.
* Memorial Plaque (medallion), issued to next-of-kin of dead British military personnel after World War I
* Pl ...
-types in
Alzheimer's disease, indicating that plaques transit different stages in their development.
Dual polarisation interferometry
Dual-polarization interferometry (DPI) is an analytical technique that probes molecular layers adsorbed to the surface of a waveguide using the evanescent wave of a laser beam. It is used to measure the conformational change in proteins, or othe ...
is an optical technique which can measure early stages of aggregation by measuring the molecular size and densities as the fibrils elongate.
These aggregate processes can also be studied on lipid bilayer constructs.
See also
*
TPM21
P24 protein family is a group of transmembrane proteins that are major components of COPI and COPII-coated vesicles. The family is also known as EMP24/GP25L/p24 family and TMP21-like proteins. The latter naming was after transmembrane emp24 domai ...
*
Sylvain Lesné – Aβ*56
References
External links
*
{{DEFAULTSORT:Beta Amyloid
Peptides
Molecular neuroscience
Alzheimer's disease
Amyloidosis
Biomarkers