Autophagy, a major lysosomal degradative pathway for organelles and long-lived or damaged proteins, Is essential for neuronal survival. We showed that neuronal autophagy is markedly defective in Alzheimer's disease (AD) and have implicated failure of lysosomal proteolysis as the key mechanism. Underscoring the pathogenic significance of autophagic-lysosomal dysregulation, we discovered that presenilin 1 (PSI) is essential for lysosomal acidification and that PS1 mutations causing AD disrupt this function. Moreover, partially restoring deficient lysosomal proteolytic function in a mouse model of amyloidosis substantially ameliorates AD-related pathology and memory deficits. Based on new evidence that APP mutations also impair autophagy, we propose In Aim 1 to define the underlying mechanism and whether or not autophagy alterations are common to APP mutations found in familial AD and App triplication in Down syndrome, and to other AD factors, e.g., cholesterol (Project 1) and cystatin C (Project 3). Contributions of upstream endocytic pathway disruption by these factors will also be explored with Projects 1, 3 and 4.
In Aim 2, consequences of impaired lysosomal proteolysis on development of AD-related neuropathology and memory defects will be investigated in mouse models and dynamically in. primary neurons using video-imaging. We found that inhibiting lysosomal proteolysis induces selective retrograde transport deficits and AD-like neuritic dystrophy. The molecular basis for these effects will be defined and evidence will be sought for a similar mechanism operating in mice expressing mutant PSI or App genes.
Aim 3 focuses on therapeutic interventions to prevent or reverse pathology and memory deficits In AD mouse models by enhancing lysosomal proteolytic efficiency. We identified a specific pharmacological class of agents able to modulate lysosomal pH Independently of vATPase, which will be defined in terms of mechanism and therapeutic efficacy in AD mouse models In comparison to new modulators of autophagy Induction. Our studies, the first to investigate autophagy systematically in AD, will firmly establish the pathogenic significance of autophagy dysfunction and identify innovative approaches to treat AD and other aging-related neurodegenerative disorders.
The proposed research aims to Identify a new class of pharmacologic agents for Alzheimer's disease based on reversing newly discovered defects In the way that AD patients break down toxic proteins that accumulate in the brain. Currently, there Is no effective treatment to slow or prevent the progression of AD and our studies have the potential of Identifying such a treatment.
|Li, Wei; Sultana, Nargis; Siraj, Nabeel et al. (2016) Autophagy dysfunction and regulatory cystatin C in macrophage death of atherosclerosis. J Cell Mol Med 20:1664-72|
|Mathews, Paul M; Levy, Efrat (2016) Cystatin C in aging and in Alzheimer's disease. Ageing Res Rev 32:38-50|
|Rosa, Elyse; Mahendram, Sujeivan; Ke, Yazi D et al. (2016) Tau downregulates BDNF expression in animal and cellular models of Alzheimer's disease. Neurobiol Aging 48:135-142|
|Colacurcio, Daniel J; Nixon, Ralph A (2016) Disorders of lysosomal acidification-The emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Res Rev 32:75-88|
|Strupp, Barbara J; Powers, Brian E; Velazquez, Ramon et al. (2016) Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer's Disease. Curr Alzheimer Res 13:97-106|
|Rao, Mala V; Campbell, Jabbar; Palaniappan, Arti et al. (2016) Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice. J Neurochem 137:253-65|
|Tiernan, Chelsea T; Ginsberg, Stephen D; Guillozet-Bongaarts, Angela L et al. (2016) Protein homeostasis gene dysregulation in pretangle-bearing nucleus basalis neurons during the progression of Alzheimer's disease. Neurobiol Aging 42:80-90|
|Kim, S; Sato, Y; Mohan, P S et al. (2016) Evidence that the rab5 effector APPL1 mediates APP-Î²CTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease. Mol Psychiatry 21:707-16|
|Jiang, Ying; Rigoglioso, Andrew; Peterhoff, Corrinne M et al. (2016) Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF. Neurobiol Aging 39:90-8|
|Morales-Corraliza, Jose; Wong, Harrison; Mazzella, Matthew J et al. (2016) Brain-Wide Insulin Resistance, Tau Phosphorylation Changes, and Hippocampal Neprilysin and Amyloid-Î² Alterations in a Monkey Model of Type 1 Diabetes. J Neurosci 36:4248-58|
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