Subcellular and metabolic examination of amyloid-β peptides in Alzheimer disease pathogenesis: Evidence for Aβ25-35

Abstract

Amyloid-β peptide (Aβ) is a central player in the pathogenesis and diagnosis of Alzheimer disease. It aggregates to form the core of Alzheimer disease-associated plaques found in coordination with tau deposits in diseased individuals. Despite this clinical relevance, no single hypothesis satisfies and explicates the role of Aβ in toxicity and progression of the disease. To explore this area, investigators have focused on mechanisms of cellular dysfunction, aggregation, and maladaptive responses. Extensive research has been conducted using various methodologies to investigate Aβ peptides and oligomers, and these multiple facets have provided a wealth of data from specific models. Notably, the utility of each experiment must be considered in regards to the brain environment. The use of Aβ25-35 in studies of cellular dysfunction has provided data indicating that the peptide is indeed responsible for multiple disturbances to cellular integrity. We will review how Aβ peptide induces oxidative stress and calcium homeostasis, and how multiple enzymes are deleteriously impacted by Aβ25-35. Understanding and discussing the origin and properties of Aβ peptides is essential to evaluating their effects on various intracellular metabolic processes. Attention will also be specifically directed to metabolic compartmentation in affected brain cells, including mitochondrial, cytosolic, nuclear, and lysosomal enzymes. © 2009 Elsevier Inc. All rights reserved.