Amyloid β (Aβ or A β) is a protein fragment of 39-43 amino acids that is the main constituent of amyloid plaques in the brains of Alzheimer's disease patients. Aβ is formed after sequential cleavage of the amyloid precursor protein (APP, transmembrane glycoprotein) by the β- and γ-secretases. The major species generated are Aβ40 and Aβ42. The latter is more hydrophobic and more apt to aggregate and thus is considered to be primarily pathogenic, consistent with the phenotype of the major familial AD-causing mutations. Increases in either total Aβ levels or the relative concentration of the 42-amino acid form have been implicated in the pathogenesis of both familial and sporadic Alzheimer's disease. The 42-mers are the most amyloidogenic form of the peptide. Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) α ATPase activity. Acts as a kinesin I membrane receptor, mediating the axonal transport of β-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu2+-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-β peptide and leading to mitochondrial dysfunction in cultured cortical neurons. β-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu2+ and Fe3+ to Cu+ and Fe2+, respectively. β-amyloid 42 is a more effective reductant than β-amyloid 40. β-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. β-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain. The γ-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis. N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).