Expression and activity of β-site amyloid precursor protein cleaving enzyme in Alzheimer's disease

Abstract

Several lines of evidence indicate that the Abeta peptide is involved at some level in the pathological process that results in the clinical symptoms of AD (Alzheimer's disease). The N-terminus of Abeta is generated by cleavage of the Met-Asp bond at position 671-672 of APP (amyloid precursor protein), catalysed by a proteolytic activity called beta-secretase. Two 'beta-secretase' proteases have been identified: BACE (beta-site APP-cleaving enzyme) and BACE2. The cause of sporadic AD is currently unknown, but some studies have reported elevated BACE/beta-secretase activity in brain regions affected by the disease. We have demonstrated that robust beta-secretase activity is also detectable in platelets that contain APP and release Abeta. This review considers the current evidence for alterations in beta-secretase activity, and/or alterations in BACE expression, in post-mortem brain tissue and platelets from individuals with AD.

BACE1 Polymorphisms Do Not Influence Platelet Membrane β-secretase Activity or Genetic Susceptibility for Alzheimer’s Disease in the Northern Irish Population

“…Previous studies have revealed an increase in b-secretase activity in postmortem brain tissue, CSF and platelets in AD (Johnston et al 2005Stockley et al 2006;Zhao et al 2007). Our previous work found no significant correlation between platelet membrane b-secretase activity and cognitive decline (MMSE score) .…”

Platelets are responsible for the accumulation of β-amyloid in blood clots inside and around blood vessels in mouse brain after thrombosis

“…Blood platelets can be an important additional source of Aβ in the brain, especially in Aβ accumulation around blood vessels, since Aβ is directly released by platelets [2, 7] or cleaved from platelet-released APP. APP, in turn, is cleaved immediately after release by APP-cleaving enzyme 1 (BACE1), located on the platelet membrane [48, 49], or by the endothelial cells of brain blood vessels [50]. MOAB-2 [NBP2-13075] (mouse IgG2b), the anti-Aβ antibody used in this study, was extensively examined previously and was found to be a pan-specific, high-titer antibody to Aβ residues 1–4, reacting with unaggregated, oligomeric, and fibrillar forms of Aβ42 and unaggregated Aβ40 as well as with aggregated amyloid in plaques [51,52].…”

“…MOAB-2 [NBP2-13075] (mouse IgG2b), the anti-Aβ antibody used in this study, was extensively examined previously and was found to be a pan-specific, high-titer antibody to Aβ residues 1–4, reacting with unaggregated, oligomeric, and fibrillar forms of Aβ42 and unaggregated Aβ40 as well as with aggregated amyloid in plaques [51,52]. MOAB-2 anti-Aβ antibody did not detect APP or its derivatives and did not colocalize with antibodies to either N- or C-terminal APP [49]. …”

Trafficking regulation of proteins in Alzheimer’s disease

“…Overexpression or downregulation of BACE1 induces or inhibits APP processing and Aβ generation both in vitro and in vivo [81-85]. Several studies find that BACE1 level and activity are elevated significantly in AD brain [86,87]. In addition, in an APP overexpression AD mouse model, deletion of BACE1 can abolish Aβ pathology and rescue cholinergic dysfunction and memory deficits [88-90].…”