Amyloid β Protein (Aβ) in Alzheimeri's Disease Brain

Abstract

Biochemical and immunocytochemical analyses were performed to evaluate the composition of the amyloid beta protein (A beta) deposited in the brains of patients with Alzheimer's disease (AD). To quantitate all A beta s present, cerebral cortex was homogenized in 70% formic acid, and the supernatant was analyzed by sandwich enzyme-linked immunoabsorbent assays specific for various forms of A beta. In 9 of 27 AD brains examined, there was minimal congophilic angiopathy and virtually all A beta (96%) ended at A beta 42(43). The other 18 AD brains contained increasing amounts of A beta ending at A beta 40. From this set, 6 brains with substantial congophilic angiopathy were separately analyzed. In these brains, the amount of A beta ending at A beta 42(43) was much the same as in brains with minimal congophilic angiopathy, but a large amount of A beta ending at A beta 40 (76% of total A beta) was also present. Immunocytochemical analysis with monoclonal antibodies selective for A beta s ending at A beta 42(43) or A beta 40 confirmed that, in brains with minimal congophilic angiopathy, virtually all A beta is A beta ending at A beta 42(43) and showed that this A beta is deposited in senile plaques of all types. In the remaining AD brains, A beta 42(43) was deposited in a similar fashion in plaques, but, in addition, widely varying amounts of A beta ending at A beta 40 were deposited, primarily in blood vessel walls, where some A beta ending at A beta 42(43) was also present. These observations indicate that A beta s ending at A beta 42(43), which are a minor component of the A beta in human cerebrospinal fluid and plasma, are critically important in AD where they deposit selectively in plaques of all kinds.

Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior

“…Apparent ADDL-like oligomeric assemblies have been isolated from postmortem AD brains and their presence correlated with memory loss [17]. In separate work, chemical stabilization of synthetic Aβ42 assembly intermediates has revealed an apparent hexamer periodicity, with hexamer, dodecamer, and octadecamer structures observed [1] In striking contrast to the properties of these various synthetic assemblies, Aβ peptides that are generated in vivo by humans and lower mammals or by cultured cells are diverse with regard to their N-and C-termini, occur naturally in extracellular fluids at low to sub-nanomolar concentrations [18,43,51,65] and can begin to assemble into metastable dimers, trimers and higher oligomers while still at low nanomolar levels. [47,67].…”

Differential Effects of a Rab6 Mutant on Secretory Versus Amyloidogenic Processing of Alzheimer's β-Amyloid Precursor Protein

“…It is now recognized that A␤ exists in a number of isoforms that include alternate carboxyl termini: e.g. A␤ and A␤ (55,56). Although A␤ 1-40 is the more abundant species, A␤ 1-42 has attracted particular attention since it is prone to form insoluble amyloid fibrils (57) and appears to be a major constituent in amyloid deposits in Alzheimer's disease (58,59).…”

Nicotine Inhibits Amyloid Formation by the β-Peptide

“…Among the various sized -peptides, the 42-residue -(1-42) peptide is the most insoluble and can act as a seed that nucleates amyloid formation Snyder et al, 1994;Tamaoka et al, 1994). The -(1-42) peptide is the predominant protein component in cerebrovascular amyloid and plaque core deposits (Roher et al, 1993;Gravina et al, 1995), and familial AD amino acid substitutions of the amyloid precursor protein favor production of the longer -(1-42) over the shorter -(1-40) peptide . Because these results implicate the -(1-42) peptide in the development of amyloid plaques, we chose to study it in our CD and precipitation studies.…”

“…The -peptide is a normal, soluble physiological component (Gravina et al, 1995). However, under certain environmental conditions, the -peptide can produce oligomeric -sheet structures that eventually precipitate as amyloid plaques (Kirschner et al, 1987;Gorévic et al, 1987;Hilbich et al, 1991;Barrow & Zagorski, 1991;Burdick et al, 1992;Terzi et al, 1994).…”