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The ion channel hypothesis of
Alzheimer’s disease Alzheimer's disease (AD) is a 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 remembering recent events. As t ...
(AD), also known as the channel hypothesis or the amyloid beta ion channel hypothesis, is a more recent variant of the amyloid hypothesis of AD, which identifies amyloid beta (Aβ) as the underlying cause of
neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...
seen in AD. While the traditional formulation of the amyloid hypothesis pinpoints insoluble, fibrillar aggregates of Aβ as the basis of disruption of
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 ...
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 subsequent apoptosis in AD, the ion channel hypothesis in 1993 introduced the possibility of an ion-channel-forming oligomer of soluble, non-fibrillar Aβ as the cytotoxic species allowing unregulated calcium influx into neurons in AD. The ion channel hypothesis is broadly supported as an explanation for the calcium ion influx that disrupts calcium ion homeostasis and induces apoptosis in neurons. Because the extracellular deposition of Aβ fibrils in
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 ...
is not sufficient to predict risk or onset of AD, and clinical trials of drugs that target the Aβ fibrillization process have largely failed, the ion channel hypothesis provides novel molecular targets for continued development of AD therapies and for better understanding of the mechanism underlying onset and progression of AD.


History

The ion channel hypothesis was first proposed by Arispe and colleagues in 1993 upon discovery that Aβ could form unregulated cation-selective ion channels when incorporated into planar
lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
s. Further research showed that a particular fragment of Aβ, Aβ (25-35), spontaneously inserts into planar lipid bilayers to form weakly selective ion channels and that membrane insertion occurs non-specifically, irreversibly, and with a broad range of oligomer conformations. Though more recent studies have found that Aβ channels can be blocked by small molecules, the broad variety of Aβ ion channel conformations and chemistries make it difficult to design a channel blocker specific to Aβ without compromising other ion channels in the cell membrane.


Structure

The Aβ
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 ...
generally assumes an α-helical formation in aqueous solution, but can reversibly transition between α-helix and β-sheet structures at varying polarities. Atomic force microscopy captured images of Aβ channel structures that facilitated calcium uptake and subsequent neuritic degeneration.
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 ...
simulations of Aβ in
lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
s suggest that Aβ adopts a β-sheet-rich structure within lipid bilayers that gradually evolves to result in a wide variety of relaxed channel conformations. In particular, data support the organization of Aβ channels in β-barrels, structural formations commonly seen in transmembrane
pore-forming toxin Pore-forming proteins (PFTs, also known as pore-forming toxins) are usually produced by bacteria, and include a number of protein exotoxins but may also be produced by other organisms such as apple snails that produce perivitellin-2 or earthwo ...
s including anthrax.


Properties

Aβ channels are selective for cations over anions, voltage-independent, and display a long channel lifetime, from minutes to hours. They can be extremely large, up to 5 nS in size, and can insert into the cell membrane from aqueous solution. Aβ channels are heterogeneous and allow flow of physiologically relevant ions such as Ca2+, Na+, K+, Cs+, and Li+ across the cell membrane.


Mechanism of action


Channel formation

Cytotoxicity caused by ion channel formation is commonly seen in the world of bacteria. While
eukaryotic Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
cells are generally less vulnerable to channel-forming toxins because of their larger volume and stiffer, sterol-containing membranes, several eukaryotic channel-forming toxins have been seen to sidestep these obstacles by forming especially large, stable ion channels or anchoring to sterols in the cell membrane. Neurons are particularly vulnerable to channel-forming toxins because of their reliance on maintenance of strict Na+, K+, and Ca2+ concentration gradients and membrane potential for proper functioning and
action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
propagation. Leakage caused by insertion of an ion channel such as Aβ rapidly alters intracellular ionic concentrations, resulting in energetic stress, failure of signaling, and cell death.


Ionic leakage

The large, poorly selective, and long-lived nature of Aβ channels allows rapid degradation of membrane potential in neurons. A single Aβ channel 4 nS in size can cause Na+ concentration to change as much as 10 μM/s. Degradation of membrane potential in this manner also generates additional Ca2+ influx through voltage-sensitive Ca2+ channels in the plasma membrane. Ionic leakage alone has been demonstrated to be sufficient to rapidly disrupt cellular homeostasis and induce cell necrosis.


Mitochondrial pathway of apoptosis

Aβ channels may also trigger apoptosis through insertion in mitochondrial membranes. Aβ injection in rats has been shown to damage mitochondrial structure in neurons, decrease mitochondrial membrane potential, and increase intracellular Ca2+ concentration. Additionally, Aβ accumulation increases expression of genes associated with the
mitochondrial permeability transition pore The mitochondrial permeability transition pore (mPTP or MPTP; also referred to as PTP, mTP or MTP) is a protein that is formed in the inner membrane of the mitochondria under certain pathological conditions such as traumatic brain injury and stro ...
(MPTP), a non-selective, high conductance channel spanning the inner and outer mitochondrial membrane. Ca2+ influx into mitochondria can collapse mitochondrial membrane potential, causing MPTP opening, which then induces mitochondrial swelling, further dissipation of membrane potential, generation of mitochondrial
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), rupture of the outer mitochondrial membrane, and release of apoptogenic factors such as cytochrome c.


Therapeutic potential


Current treatments

The only treatments currently approved for AD are either cholinesterase inhibitors (such as
donepezil Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to ...
) or glutamate receptor antagonists (such as
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 ...
), which show limited efficacy in treating symptoms or halting progression of AD. The slight improvement in cognitive function brought about by these drugs is only seen in patients with mild to moderate AD, and is confined to the first year of treatment, as efficacy progressively declines, completely disappearing by 2 or 3 years of treatment. Extensive research has gone into the design of potential AD treatments to reduce Aβ production or aggregation, but these therapeutics have historically failed in Phase III clinical trials. The ion channel hypothesis of AD provides a novel avenue for development of AD therapies that may more directly target the underlying pathophysiology of AD.


Channel blockers

Nonspecific Aβ channel blockers including
tromethamine Tris, or tris(hydroxymethyl)aminomethane, or known during medical use as tromethamine or THAM, is an organic compound with the formula (HOCH2)3CNH2, one of the twenty Good's buffers. It is extensively used in biochemistry and molecular biology as ...
(Tris) and Zn2+ have successfully inhibited Aβ cytotoxicity. Least-energy molecular models of the Aβ channel have been used to create polypeptide segments to target the mouth of the Aβ pore, and these selective Aβ channel blockers have also been shown to inhibit Aβ cytotoxicity. Structural modeling of Aβ channels, however, suggests that the channels are highly polymorphic, with the ability to move and change size and shape within the lipid membrane. The broad range of conformations adopted by the Aβ channel makes design of a specific, highly effective Aβ channel blocker difficult.


Membrane hyperpolarization

Indirect methods such as membrane hyperpolarization may help limit the cytotoxic
depolarizing In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
effects of Aβ channels. Potassium ATP channel activation has been demonstrated to attenuate Ca2+ influx and reduce
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 ...
in neurons, as well as to improve memory and reduce Aβ and
tau Tau (uppercase Τ, lowercase τ, or \boldsymbol\tau; el, ταυ ) is the 19th letter of the Greek alphabet, representing the voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300. The name in English ...
pathology in a
transgenic A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
AD mouse model. Similarly, drugs that block voltage-gated Ca2+ channels have also been shown to protect neurons from Aβ toxicity.


Other amyloid channels

Several other classes of
amyloid 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 huma ...
proteins also form ion channels, including proteins implicated in
type II diabetes mellitus Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination ...
, prion diseases,
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, and
Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
. Consistent with Aβ channels, other amyloid channels have also been reported to be large, non-selective, voltage-independent, heterogeneous, and irreversible. These distinct properties set amyloid channels apart from other ion channels in neurons and facilitate unregulated ionic leakage resulting in cell depolarization, disruption of ion homeostasis, and cell death. Further investigation of amyloid proteins and the cytotoxic effects of amyloid channel formation is necessary for development of drug candidates that are able to selectively block amyloid channels or bind them prior to membrane insertion, an area of research that may prove highly relevant to not just AD but a wide variety of other diseases.


References

{{reflist, 2 Alzheimer's disease research Biological hypotheses Ion channels