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Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM ('a disintegrin and metalloprotease domain') family, which are expressed on the surfaces of cells and anchored in the cell membrane .
p3 peptide is a product of non-amyloidogenic APP processing. p3 peptide is known to have a role in AD and DS , however it has not been clearly determined yet. In order to study the function of p3 peptide in AD, specific antibodies’ location techniques have been used to determine its absence or sparseness in aged non-AD brains.
The amyloidogenic processing of APP has been linked to its presence in lipid rafts. When APP molecules occupy a lipid raft region of membrane, they are more accessible to and differentially cleaved by beta secretase, whereas APP molecules outside a raft are differentially cleaved by the non-amyloidogenic alpha secretase. [31]
SNX8 has a neuroprotective role related to AD: it enhances the non-amyloidogenic APP pathway and, hence, reduces the Aβ plaques and deposit accumulations and suppresses cognitive impairment caused by AD. Some studies found that SNX8 levels were drastically lower in patients with AD.
To date, 37 human proteins have been found to form amyloid in pathology and be associated with well-defined diseases. [2] The International Society of Amyloidosis classifies amyloid fibrils and their associated diseases based upon associated proteins (for example ATTR is the group of diseases and associated fibrils formed by TTR). [3]
The second pathway is the non-amyloidogenic pathway and does not produce Aβ. [19] In the amyloidogenic pathway, APP (the parent protein) is trafficked to endosomes, cleaved by beta-secretase (BACE), after which it moves back to the cell surface to be cleaved by gamma secretase thus releasing the Aβ peptide.
[66] β- and γ-secretases cleave APP into Aβ in the amyloidogenic pathway whereas α- and γ-secretase inhibit Aβ generation in the non-amyloidogenic pathway. [66] β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase important for Aβ generation. [66]
The normal function of Aβ is not yet known. [9] Though some animal studies have shown that the absence of Aβ does not lead to any obvious loss of physiological function, [10] [11] several potential activities have been discovered for Aβ, including activation of kinase enzymes, [12] [13] protection against oxidative stress, [14] [15] regulation of cholesterol transport, [16] [17] functioning ...