Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease

Abstract

SPECIFIC AIMSThere have been many postulated links between mitochondrial function/dysfunction and Alzheimer’s disease (AD) over the years. Recent studies have emphasized a role for intracellular amyloid-β peptide (Aβ) in cytotoxicity of amyloidogenic material. Based on this, we sought to determine whether Aβ might be associated with mitochondria.PRINCIPAL FINDINGS1. Aβ is associated with mitochondria of transgenic (Tg) mice expressing human mutant amyloid precursor protein (mAPP) under control of a promoter directing its expressing to neurons in the central nervous system (PDGF B chain promoter)Accumulation of Aβ occurs in a time-dependent manner (most rapidly during the time interval from 4 to 12 months of age), appears to strongly favor deposition of Aβ (1-42) vs. the shorter 40 amino acid forms, and occurs in parts of the brain affected by AD-type pathology. These conclusions result from morphologic (confocal and immunoelectron microscopy) and biochemical (immunoblotting on isolated mitochondria) exper...