Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease

Abstract

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

Small heat-shock proteins: important players in regulating cellular proteostasis

“…Amyloid plaques are composed primarily of A peptides which are derived from the abnormal processing of -amyloid precursor protein by -secretase. In patients with familial AD, overproduction of A leads to early onset AD [182][183][184][185]. The level of Bc expression in brains of patients suffering AD is markedly increased compared to that in the normal human brain [105,186] presumably due to the cellular stress caused by disease.…”

The genetics and pathophysiology of Alzheimer's disease

“…Interestingly, no differences were seen between A␤ release from cells derived from presymptomatic or symptomatic mutation carriers, indicating that increased A␤ production precedes onset of symptoms. Furthermore, both A␤ 1-40 and A␤ 1-42 were increased in plasma from symptomatic and presymptomatic mutation-carriers from the Swedish family [26]. Also, cultured fibroblasts bearing different presenilin mutations release increased levels of A␤ 1-42 into the cell medium [26].…”

“…Furthermore, both A␤ 1-40 and A␤ 1-42 were increased in plasma from symptomatic and presymptomatic mutation-carriers from the Swedish family [26]. Also, cultured fibroblasts bearing different presenilin mutations release increased levels of A␤ 1-42 into the cell medium [26]. A␤ 1-42 has been shown to be the A␤ variant most prone to aggregate, and A␤ 1-42 can also seed aggregation of the more soluble A␤ 1-40 into fibrils [27].…”

“…Thus, these studies strongly suggest that altered balance of APP processing favouring A␤ 1-42 production provides the link between APP and presenilin mutations and the clinical Alzheimer phenotype in these families. APP and presenilin mutations have one common denominator: they all increase A␤ 1-42 production [26].…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…Congophilic A β is detected in up to 70% of IBM muscle fibers and mostly found in nonvacuolated areas 188. A β peptides are generated via the sequential cleavage of the transmembrane glycoprotein APP by the protease β ‐site of the APP cleaving enzyme 1 (BACE1) and the γ ‐secretase complex 189, 190, 191. Components of the sequential cleavage machinery of APP, such as BACE1, are upregulated in IBM muscle 192, 193.…”