The role of cerebral amyloid   accumulation in common forms of Alzheimer disease

Abstract

For approximately 80 years following Alzheimer's description of the disease that bears his name, a gulf divided researchers who believed that extracellular deposits of the amyloid β (Aβ) peptide were pathogenic from those who believed that the deposits were secondary detritus. Since 1990, the discoveries of missense mutations in the Aβ peptide precursor (APP) and the APP-cleaving enzyme presenilin 1 (PS1) have enabled much progress in understanding the molecular, cellular, and tissue pathology of the aggregates that accumulate in the interstices of the brains of patients with autosomal dominant familial Alzheimer disease (AD). Clarification of the molecular basis of common forms of AD has been more elusive. The central questions in common AD focus on whether cerebral and cerebrovascular Aβ accumulation is (a) a final neurotoxic pathway, common to all forms of AD; (b) a toxic by-product of an independent primary metabolic lesion that, by itself, is also neurotoxic; or (c) an inert by-product of an independent primary neurotoxic reaction. Antiamyloid medications are entering clinical trials so that researchers can evaluate whether abolition of cerebral amyloidosis can mitigate, treat, or prevent the dementia associated with common forms of AD. Successful development of antiamyloid medications is critical for elucidating the role of Aβ in common AD.

Neuropathology for the Neuroradiologist: Plaques and Tangles

“…Curiously, the name "amyloid" (derived from Latin "amylum" or starch), as coined by the famous German pathologist and statesman, Rudolph Ludwig Karl Virchow (1821-1902), is a misnomer, because he thought the protein was actually a starchlike compound, due to its behavior with periodic-acid-Schiff stain. 25 In addition to the A␤ peptide, plaques also contain a variety of other components such as apolipoprotein E, ␣-1-antichymotrypsin, and proteoglycans. 18,24 Associated with many of the plaques is evidence of inflammation and abnormal neuronal processes called dystrophic neurites.…”

“…41,45,50 A␤-42, which normally constitutes only 5%-10% of all A␤ peptides, tends to aggregate more aggressively than the A␤-40 when it is present in higher concentrations. 25 Similarly, mutations in a related protein presenilin 2 also cause a form of autosomal dominant AD. 41,45,50 Polymorphism of the gene coding for apolipoprotein E, a protein involved in transport and metabolism of lipids, alters one's risk for DAT.…”

Alleviation of Aβ-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model

“…1 Ab deposited in senile plaques is considered to be primarily involved in the pathogenesis of AD, because (1) familial AD has been linked to mutations in the amyloid precursor protein (APP) 2 and (2) familial AD-linked mutations in the APP and presenilin genes result in increased production of Ab42, which is the predominant form found in senile plaques. 2 Levels of total Ab40 and Ab42 are elevated early in dementia, and levels of both peptides are strongly correlated with cognitive decline. 3 A new approach is required, because current pharmacological therapy directed at symptomatic relief has proved to be marginally effective.…”

The Correlation between Genotype and Phenotype of Alzheimer's Disease

“…For example, the majority of the FAD-associated mutations in APP lie close to its γ-secretase site, such as the French (p.V715M) [10], German (p.V715A) [11], Florida(p.I716V) [12], London (p.V717I) [9] and Indiana (p.V717F) [13] mutations, which result in a relative increase in the production and deposition of the more fibrillogenic form of Aβ, Aβ42 [5]. Although the French (p.V715M) mutation results in a reduction of Aβ40 without affecting Aβ42 production, suggesting that it is the increase in the ratio of Aβ42 to Aβ40 that is important rather than the absolute amount of Aβ42.…”