Increasing evidence indicates that intracellular accumulation of amyloid-beta peptide (Abeta) is a key factor in neuronal perturbation. However, critical intracelluar mechanisms through which Abeta impairs cellular properties resulting in neuronal dysfunction remain to be elucidated. Working during the past grant period supports a link between ABAD and Abeta-mediated mitochondrial dysfunction relevant to AD: early defects of mitochondrial function. ABAD-AB complex was found in mitochondria of transgenic (Tg) mice with targeted neuronal expression of mutant APR and ABAD. We have found unexpected localization of Abeta in mitochondria. Our pilot study, using both of biochemical and morphologic methods (immunoblotting, double immunostaining with confocal microscope and immunoelectron microscopy) demonstrated Abeta in mitochondria from human AD brain and from transgenic (Tg) mice with targeted neuronal overexpression of mutant human amyloid precursor protein (Tg mAPP). Furthermore, we have observed translocation of Abeta from endpplasmic reticulum (ER) to the mitochondria in primary cortical neurons cultured from brains of Tg mAPP mice. Mitochondrial dysfunction was observed in isolated mitochondria and brains of Tg mAPP mice as compared with nonTg littlemates. We postulate that the basic mechanisms underlying these observations is Aft-induced perturbation of the membrane permeability transition pore (MPTP) due to two events: increased association of cyclophilin D (CypD) with the inner mitochondrial membrane (i.e., interaction with components of the MPTP), and enhanced association of bax with the outer mitochondrial membrane (thereby altering permeability of the outer membrane as well as MPTP), which triggers activation caspase pathway and cytochrome c release leading to neuronal apoptosis.
Our specific aims are: 1) To delineate parameters of Abeta localization to mitochondria and to correlate levels of Abeta in mitochondria with mitochondrial function in AD-affected brain regions as compared with spared-regions; 2) To determine the mechanism of AB import into mitochondria; 3) To determine mechanisms of Abeta-mediated mitochondrial dysfunction; 4) To analyze the contribution of Bax to Abeta-induced cell stress in vivo using transgenic mice. This competitive renewal is based on the hypothesis that mitochondria provide a site for accumulation of intraneuronal Abeta which potentiates organelle dysfunction leading to neuronal perturbation in Alzheimer's disease. The proposed studies would provide a new intracellular pathway potentially leading to neuronal dysfunction relevant to AD.
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