Amyloid β-Protein Toxicity and the Pathogenesis of Alzheimer Disease

Abstract

Although amyloid deposition was noted by Alzheimer in 1907 (1), it has been only 17 years since the toxicity of A␤ 2 was first described (2). The prevailing view through most of the twentieth century was that A␤ is a marker of disease progression in AD but does not play a role in the neurodegenerative process. This view changed in the 1990s with the articulation of the amyloid hypothesis, which posits that abnormal accumulation of A␤ in the brain is a direct cause of neurodegeneration and cognitive decline in AD. The hypothesis is supported by the identification of mutations in APP (3) and presenilins 1 and 2 (4 -7) that increase A␤ generation or, more importantly, the generation of a minor 42-amino acid form (A␤42) with an increased propensity for aggregation (8). This review sets forth the major lines of evidence for A␤ toxicity and focuses on the interface between A␤ toxicity and molecular mechanisms of synaptic plasticity. Do Plaques Matter?The early studies of Blessed and co-workers (9) suggested that plaque numbers were directly related to quantitative measures of cognitive decline in the aged population. However, subsequent studies carried out by Terry et al. (10) cast doubt on the predictive value of plaque numbers, suggesting instead that NFTs and synapse loss were more reliable predictors of cognitive decline. Moreover, plaque formation is a common feature of the aging human brain that can occur in the absence of cognitive decline (11). More recently, it has been suggested that accumulation of toxic oligomers of A␤ may be more relevant than plaques to mechanisms involved in cognitive decline.Transgenic mouse models expressing APP and presenilin variants associated with FAD have provided important insights into structural, neurophysiological, and behavioral effects of A␤ accumulation in the brain (12). Multiphoton imaging studies have demonstrated disrupted neurites and decreased spine density in association with fibrillar A␤ deposits in the Tg2576 transgenic mouse model that expresses the APPsw mutation (13,14). In addition, stereologic mapping of neuronal cell density showed some degree of neuronal loss in the immediate vicinity of A␤ deposits (15). The neuritic dystrophy observed in APP transgenic mice appears to be directly related to the fibrillar component of A␤ deposits. When the APP transgenic was placed on an apoE-deficient background, A␤ deposition still occurred, but fibrillar deposits were absent, and neuritic dystrophy was markedly reduced. When apoE3 or apoE4 was expressed, fibrillar A␤ deposits appeared with concomitant neuritic degeneration that was greater for apoE4 than for apoE3 (16,17). However, it was unclear from these studies which came first, neuritic degeneration or deposition of fibrillar A␤. Another study suggested that axonal dystrophy and altered axonal transport occur early in AD and may lead to amyloid deposition (18). The question of which comes first, amyloid or neuritic dystrophy, was recently addressed by in vivo multiphoton microscopy in an APPswe/PS1d9XYFP transgeni...

Truncated Amyloid-β(11–40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly

“…The amyloidogenicity of A␤ sequences is often thought to correlate with disease progression. A␤ forms fibers much faster than A␤ and is also more toxic in vivo (61)(62)(63)(64). The heightened rate of fiber nucleation and elongation observed for A␤ (11-40/42) may be caused by the loss of negatively charged side chains, as it is known that the pI and charge of A␤ have a profound influence on its rate of fiber formation (22,65).…”

Calcium Signaling and Amyloid Toxicity in Alzheimer Disease

“…Associations between naturally produced A␤ oligomers and AD pathology were made by Selkoe and co-workers (90), who identified a naturally secreted species of A␤ aggregates capable of disrupting neuronal plasticity. Soluble A␤ oligomers extracted from AD patients inhibit longterm potentiation, enhance long-term depression, and trigger dendritic spine reduction in rodent hippocampus (17,91). These pathological effects were shown to be specifically attributable to A␤ 1-42 dimers.…”

Wine consumption, cognitive function and dementias – A relationship?

“…Amyloid-␤ (A␤) is a core component of the plaque or lesion found in the neocortex and hippocampus of brains affected by Alzheimer's disease [117,125,126]. It is formed after sequential proteolytic cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein.…”