Biochemistry of amyloid β-protein and amyloid deposits in Alzheimer disease

Abstract

Progressive cerebral deposition of the amyloid β-protein (Aβ) in brain regions serving memory and cognition is an invariant and defining feature of Alzheimer disease. A highly similar but less robust process accompanies brain aging in many nondemented humans, lower primates, and some other mammals. The discovery of Aβ as the subunit of the amyloid fibrils in meningocerebral blood vessels and parenchymal plaques has led to innumerable studies of its biochemistry and potential cytotoxic properties. Here we will review the discovery of Aβ, numerous aspects of its complex biochemistry, and current attempts to understand how a range of Aβ assemblies, including soluble oligomers and insoluble fibrils, may precipitate and promote neuronal and glial alterations that underlie the development of dementia. Although the role of Aβ as a key molecular factor in the etiology of Alzheimer disease remains controversial, clinical trials of amyloid-lowering agents, reviewed elsewhere in this book, are poised to resolve the question of its pathogenic primacy.

Figure 1.

Three-dimensional reconstructed image by confocal microscopy of a neuritic (senile) plaque in the cortex of a patient dying with Alzheimer disease. Red labeling is by an antibody to amyloid β-protein which reveals the extracellular amyloid; green labeling is with an antibody against p-Tau which reveals intimately associated dystrophic neurites. Note that this plaque core is not a solid mass of amyloid but is fragmented and porous and contains abnormal cell processes intercalated within it. (Image courtesy of Dr. Eliezer Masliah, University of California, San Diego, CA.)

Figure 2.

Model of potential interactions of Aβ_18-41 dimer with membrane lipid bilayers. The hydrophobic dimer–dimer interface of the Aβ_18-41 tetramer is intercalated into the membrane surface through non-electrostatic interactions, whereas hydrophilic aspects (blue) with metal-binding sites (black) are on the membrane surface. (From Streltsov et al. 2011; reprinted, with permission, from the author.)

Figure 3.

Representative western blots showing Aβ in frontal cortex of selected Alzheimer disease (AD) and control subjects. (A) Soluble Aβ in 175,000 g supernatants after a single extraction in phosphate-buffered saline. (B) Insoluble Aβ extracted from the 175,000 g pellets. (C) To enable quantification and between-gel comparisons, synthetic Aβ₄₀ standard curves were run on each gel. The markers designate monomeric (4 kDa), dimeric (8 kDa), and trimeric (12 kDa) forms of Aβ. (From McLean et al. 1999; reprinted, with permission, from the author.)