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.
|Bravo, Francisca Vaz; Da Silva, Jorge; Chan, Robin Barry et al. (2018) Phospholipase D functional ablation has a protective effect in an Alzheimer's disease Caenorhabditis elegans model. Sci Rep 8:3540|
|Ramsey, Christine M; Gnjidic, Danijela; Agogo, George O et al. (2018) Longitudinal patterns of potentially inappropriate medication use following incident dementia diagnosis. Alzheimers Dement (N Y) 4:1-10|
|Grivel, Margaux M; Leong, Wei; Masucci, Michael D et al. (2018) Impact of lifetime traumatic experiences on suicidality and likelihood of conversion in a cohort of individuals at clinical high-risk for psychosis. Schizophr Res 195:549-553|
|Hadjichrysanthou, Christoforos; McRae-McKee, Kevin; Evans, Stephanie et al. (2018) Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. J Alzheimers Dis 66:587-600|
|Hanfelt, John J; Peng, Limin; Goldstein, Felicia C et al. (2018) Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center. Neurobiol Dis 117:62-71|
|Zhou, Zilu; Wang, Weixin; Wang, Li-San et al. (2018) Integrative DNA copy number detection and genotyping from sequencing and array-based platforms. Bioinformatics 34:2349-2355|
|Burke, Shanna L; Hu, Tianyan; Fava, Nicole M et al. (2018) Sex differences in the development of mild cognitive impairment and probable Alzheimer's disease as predicted by hippocampal volume or white matter hyperintensities. J Women Aging :1-25|
|Wang, Qi; Guo, Lei; Thompson, Paul M et al. (2018) The Added Value of Diffusion-Weighted MRI-Derived Structural Connectome in Evaluating Mild Cognitive Impairment: A Multi-Cohort Validation1. J Alzheimers Dis 64:149-169|
|Wang, Tingyan; Qiu, Robin G; Yu, Ming (2018) Predictive Modeling of the Progression of Alzheimer's Disease with Recurrent Neural Networks. Sci Rep 8:9161|
|Agogo, George O; Ramsey, Christine M; Gnjidic, Danijela et al. (2018) Longitudinal associations between different dementia diagnoses and medication use jointly accounting for dropout. Int Psychogeriatr 30:1477-1487|
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