Amyloid-beta precursor protein

It functions as a cell surface receptor[5] and has been implicated as a regulator of synapse formation,[6] neural plasticity,[7] antimicrobial activity,[8] and iron export.

[16] The amyloid beta region of the protein, located in the membrane-spanning domain, is not well conserved across species and has no obvious connection with APP's native-state biological functions.

[28] The differential expression of these isoforms plays a significant role in cellular processes such as neurodevelopment, synaptic plasticity, and the pathogenesis of Alzheimer's disease.

APP undergoes extensive post-translational modification including glycosylation, phosphorylation, sialylation, and tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments.

[16] Cleavage by gamma secretase within the membrane-spanning domain after beta-secretase cleavage generates the amyloid-beta fragment; gamma secretase is a large multi-subunit complex whose components have not yet been fully characterized, but include presenilin, whose gene has been identified as a major genetic risk factor for Alzheimer's.

[33] Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive.

The most-substantiated role for APP is in synaptic formation and repair;[6] its expression is upregulated during neuronal differentiation and after neural injury.

[16] In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.

[35] On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.

The control beads were not motile, which demonstrated that the terminal COOH moiety of peptides is not sufficient to mediate transport.

[44] The amyloid-β precursor protein (AβPP), and all associated secretases, are expressed early in development and play a key role in the endocrinology of reproduction – with the differential processing of AβPP by secretases regulating human embryonic stem cell (hESC) proliferation as well as their differentiation into neural precursor cells (NPC).

[49] It is postulated that the loss of sex steroids (including progesterone) but the elevation in luteinizing hormone, the adult equivalent of hCG, post-menopause and during andropause drives amyloid-β production[50] and re-entry of post-mitotic neurons into the cell cycle.

(a) A low magnification image immediately after co-injection of red negatively charged and green glycine-conjugated beads showing the injection site, marked with an oil droplet, appearing as a round yellow sphere. Overlap of red and green fluorescence produces a yellow image. (b) At 50 min after injection, the red carboxylated beads have progressed in the anterograde direction (to the right) while the green glycine-conjugated beads have made no progress. (c)–(e) An axon co-injected with red APP-C beads and green glycine beads and imaged for 100 frames at 4 s intervals at 40× magnification. (c) Red channel (left) first frame; (center) 50 frames superimposed; (right) all 100 frames superimposed. Note the progression of individual beads towards the right, anterograde, side of the injection site heading towards the presynaptic terminal. (d) Two images of the green channel from the same video sequence; (left) first frame; (center) 100 frames superimposed. Note the lack of significant movement of the green glycine beads. (e) Both red and green channels from 100 frames superimposed of the same video as in (c) and (d). (f) Single bead trajectories at high magnification from a set of superimposed frames showing movements of beads.
The metal-binding domain of APP with a bound copper ion. The side chains of the two histidine and one tyrosine residues that play a role in metal coordination are shown in the Cu(I) bound, Cu(II) bound, and unbound conformations, which differ by only small changes in orientation.
The extracellular E2 domain, a dimeric coiled coil and one of the most highly conserved regions of the protein from Drosophila to humans. This domain, which resembles the structure of spectrin , is thought to bind heparan sulfate proteoglycans . [ 23 ]
Amyloid-beta precursor protein exon 7 & 8 dependent transcript variant abundance (Transcript variant groups containing major transcript variant 1, 2, 3 and, 11) in the immature (proliferative) SH-SY5Y cells and SH-SY5Y derived post-mitotic neurons. [ 28 ]