Beta amyloid

amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
Processing of the amyloid precursor protein
Identifiers
Symbol APP
Alt. symbols AD1
Entrez 351
HUGO 620
OMIM 104760
RefSeq NM_000484
UniProt P05067
Other data
Locus Chr. 21 q21.2
Beta-amyloid peptide (beta-APP)
solution structure of the methionine-oxidized amyloid beta-peptide (1-40). does oxidation affect conformational switching? nmr, 10 structures
Identifiers
Symbol Beta-APP
Pfam PF03494
InterPro IPR013803
SCOP 1ba4

Amyloid beta (Aβ or Abeta) is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease. Evidence has been found that Aβ has multiple non-disease activities.[1]

Contents

Normal Activity of Aβ

Several potential activities have been discovered for Aβ that are not associated with disease, including activation of kinase enzymes,[2][3] protection against oxidative stress[4][5] regulation of cholesterol transport[6][7] functioning as a transcription factor,[8][9] and anti-microbial activity (potentially associated with Aβ's pro-inflammatory activity).[10]

Disease Associations

Aβ is the main component of amyloid plaques (deposits found in the brains of patients with Alzheimer's disease). Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis (a muscle disease), while Aβ can also form the aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy. The plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers,[11] a protein fold shared by other peptides such as the prions associated with protein misfolding diseases. Recent research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer's disease.[12]

Formation

Aβ is formed after sequential cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein of undetermined function. APP can be processed by α-, β- and γ-secretases; Aβ protein is generated by successive action of the β and γ secretases. The γ secretase, which produces the C-terminal end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 36-43 amino acid residues in length. The most common isoforms are Aβ40 and Aβ42; the shorter form is typically produced by cleavage that occurs in the endoplasmic reticulum, while the longer form is produced by cleavage in the trans-Golgi network.[13] The Aβ40 form is the more common of the two, but Aβ42 is the more fibrillogenic and is thus associated with disease states. Mutations in APP associated with early-onset Alzheimer's have been noted to increase the relative production of Aβ42, and thus one suggested avenue of Alzheimer's therapy involves modulating the activity of β and γ secretases to produce mainly Aβ40.[14]

Genetics

Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease (familial AD). This form of AD only accounts for no more than 10% of all cases, and the vast majority of AD is not accompanied by such mutations.[15] However, familial Alzheimer disease is likely to result from altered proteolytic processing. 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)[16] have been implicated in the pathogenesis 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 KLVFFAAE is known to form amyloid on its own, and probably forms the core of the fibril.

The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is by no means conclusively established. Intra-cellular deposits of tau protein are also seen in the disease, and may also be implicated. The oligomers that form on the amyloid pathway, rather than the mature fibrils, may be the cytotoxic species.[17]

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 (APPE693Q) develop the disease. Furthermore mice that are in addition engineered to convert oligomers into plaques (APPE693Q X PS1ΔE9), are no more impaired than the oligomer only mice.[18]

Structure

Amyloid beta is intrinsically unstructured, meaning that in solution it does not acquire a compact 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 and molecular dynamics. 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.[19] Replica exchange molecular dynamics studies suggested that amyloid beta can indeed populate multiple discrete structural states;[20] more recent studies identified a multiplicity of discrete conformational clusters by statistical analysis.[21] By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states,[22] with the C-terminus of amyloid beta 1-42 being more structured than that of the 1-40 fragment.

Structural information on the oligomeric state of amyloid beta is still sparse as of 2010. Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure.[23] 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;[24] computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.[25]

Intervention strategies

Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:[26]

There is some indication that supplementation of the hormone melatonin may be effective against amyloid. Melatonin interacts with amyloid beta and inhibits its agregation[29][30][31] This anti-aggregatory activity occurs only through an interaction with dimers of the soluble amyloid beta peptide. Melatonin does not reverse fibril formation or oligomers of amyloid beta once they are formed. This is supported by experiments in transgenic mice which suggest that melatonin has the potential to prevent amyloid deposition if administered early in life, but it may not be efficacious to revert amyloid deposition or treat Alzheimer's disease.

This connection with melatonin, which regulates sleep, is strengthened by the recent research showing that the wakefulness inducing hormone orexin influences amyloid beta (see below).[32]. Interestingly, animal experiments show that melatonin may also correct mild elevations of cholesterol which is also an early risk factor for amyloid formation.

The cannabinoid HU-210 has been shown to prevent amyloid beta-promoted inflammation.[33]

Circadian rhythm of amyloid beta

A 2009 report has just shown that amyloid beta production follows a circadian rhythm, rising when an animal (mouse) or person is awake and falling during sleep.[32] The wakefulness-promoting neuroprotein orexin was shown to be necessary for the circadian rhythm of amyloid beta production.[32] The report suggested that excessive periods of wakefulness (i.e. due to sleep debt) could cause chronic build-up of amyloid beta, which could hypothetically lead to Alzheimer's disease.[32] This is consistent with recent findings that chronic sleep deprivation is associated with early onset Alzheimer's disease.

Melatonin is also involved in circadian rhythm maintenance. Notably, melatonin has been connected with the "sundowning" phenomenon, in which Alzheimer's disease patients that have amyloid plaques in the hypothalamus exhibit exacerbation of Alzheimer's disease symptoms late in the day.[34] This "sundowning" phenomenon could be directly or indirectly related to the recently discovered continuous increase in amyloid beta throughout the day.

Measuring amyloid beta

There are many different ways to measure Amyloid beta. It can be measured semi-quantitatively with immunostaining, which also allows one to determine location. Amyloid beta may be primarily vascular, as in cerebral amyloid angiopathy, or in senile plaques and vascular.

One highly sensitive method is ELISA which is an immunosorbent assay which utilizes a pair of antibodies that recognize Amyloid beta.

Imaging compounds, notably Pittsburgh Compound-B, (BTA-1, a thioflavin), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET imaging, has been used to image areas of plaque deposits in Alzheimer's patients.

Atomic force microscopy, which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of Amyloid beta in vitro.[35]

Dual polarisation interferometry is an optical technique which can measure the very earliest stages of aggregration and inhibition by measuring the molecular size and densities as the fibrils elongate.[36][37] These aggregate processes can also be studied on lipid bilayer constructs.[38]

References

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Further reading

External links

Common amyloid forming proteins
Systemic amyloidosis
Organ-limited amyloidosis