Amyloid beta
Amyloid beta peptide (beta-APP) | |||||||||
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TCDB 1.C.50 | | ||||||||
OPM superfamily | 304 | ||||||||
OPM protein | 2y3k | ||||||||
Membranome | 45 | ||||||||
|
amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | |||||||
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Chr. 21 q21.2 | |||||||
|
Amyloid beta (Aβ or Abeta) denotes
A study has suggested that APP and its amyloid potential is of ancient origins, dating as far back as early
Normal function
The normal function of Aβ is not well understood.[8] Though some animal studies have shown that the absence of Aβ does not lead to any obvious loss of physiological function,[9][10] several potential activities have been discovered for Aβ, including activation of kinase enzymes,[11][12] protection against oxidative stress,[13][14] regulation of cholesterol transport,[15][16] functioning as a transcription factor,[17][18] and anti-microbial activity (potentially associated with Aβ's pro-inflammatory activity).[19][20][21]
The glymphatic system clears metabolic waste from the mammalian brain, and in particular amyloid beta.[22] 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[23] and presequence protease.[24] The rate of removal is significantly increased during sleep.[25] However, the significance of the glymphatic system in Aβ clearance in Alzheimer's disease is unknown.[26]
Disease associations
Aβ is the main component of
Alzheimer's disease
Research suggests that soluble oligomeric forms of the amyloid beta may be causative agents in the development of Alzheimer's disease.[30] It is generally believed that Aβ oligomers are the most toxic.[31] Several 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.[32][33]
Brain Aβ is elevated in people with sporadic Alzheimer's disease. Aβ is the main constituent of brain
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)[41] 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 KLVFFAE is known to form amyloid on its own, and probably forms the core of the fibril.[citation needed] 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.[42]
The "
Cancer
While Aβ has been implicated in
Down syndrome
Adults with Down syndrome 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.[46]
Formation
Aβ is formed after sequential
Genetics
Autosomal-dominant mutations in APP cause hereditary
The gene for the amyloid precursor protein is located on
Structure and toxicity
Amyloid beta is commonly thought to be
Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure.[59] 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;[60] computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.[61]
Immunotherapy research
Immunotherapy may stimulate 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 were tested in clinical trials included aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab.[62][63]
Measuring amyloid beta
Imaging compounds, notably Pittsburgh compound B, (6-OH-BTA-1, a thioflavin), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET imaging, is used to image areas of plaque deposits in those with Alzheimer's.[64]
Post mortem or in tissue biopsies
Amyloid beta can be measured semiquantitatively with
One sensitive method is
See also
- TPM21
- Sylvain Lesné – Aβ*56
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