HIV-associated neurocognitive disorders (HAND), which persist in up to 50% of HIV+ patients despite viral suppression by antiretroviral therapy (ART) has certain clinical and pathological features in common with Alzheimer?s Disease (AD). In an aging HIV+ population it is increasingly difficult to distinguish AD from the combined effects of age and HIV. In AD, increased amyloid precursor protein (APP) cleavage by ?-site amyloid precursor protein cleaving enzyme-1 (BACE1) leads to amyloid-? (A?) overproduction that can ultimately form extracellular plaques. In HAND, despite mixed evidence of a role for A?, numerous studies reported altered APP processing and metabolism, even in patients on effective ART regimens. Several of the pathologic processes shared between HAND and AD can trigger endoplasmic reticulum (ER) stress, which leads to unfolded protein response (UPR). Most pertinent here, PERK-mediated phosphorylation of eIF2? slows global translation while selectively enhancing translation of a subset of genes including BACE1, whereas eIF2? suppression can alleviate AD-associated memory deficits in rodents. We previously demonstrated UPR activation in HAND prefrontal cortex and increased BACE1 in cortex of HIV+ patients. Our collaborator Dr. Schellenberg has linked a specific haplotype of PERK, PERK*B, which contains 3 protein-coding single nucleotide polymorphisms (SNPs) resulting in increased kinase activity, to an increased risk for progressive supranuclear palsy. Our preliminary analysis from a GWAS study of 1049 patients in the CHARTER cohort revealed that 3 PERK*B- associated SNPs significantly correlated with worse global deficit scores. In our currently funded R01, we are examining if PERK*B haplotype resulting from 3 SNPs, which may confer increased kinase activity, may underlie the alteration/s of PERK?s protein function and/or changes in its amount. In the parent grant, our aims are determining 1) the mechanisms of PERK-mediated neurotoxicity in vitro, 2) the mechanisms of PERK-mediated neuronal injury in a small animal model of HIV-induced gliosis, and 3) if PERK is a HAND modulator through inheritance of a genetic haplotype, and/or chronic activation. Based on the shared mechanisms between HAND and AD, data supporting involvement of the PERK pathway and BACE1 upregulation in pathogenesis of both diseases, and accumulating evidence implicating PERK*B variant as a predictive risk factor in diseases with similar cognitive and pathological features, we propose to extend our studies to dissect the role of PERK*B in AD by crossing PERK*B transgenic line with the APP/PS1 transgenic and APP-DSL knock-in mouse models. This study will address the urgent need for identification of risk factors and biomarkers as predictive markers for AD. This proposal to expand our currently funded award to develop a new research direction focused on AD and related dementias does not include new activity or methods, is within the scope of the currently funded parent R01 and aims to ultimately address high-priority topics for both AD and HAND including shared pathways of degeneration and genetic markers as predictive risk factors and disease modulators.

Public Health Relevance

Alzheimer's disease is the most common form of dementia among the elderly, affecting approximately 15% of individuals between the ages of 65 and 74 and 44% of those between the ages of 75 and 84 in the US. Current treatments for Alzheimer's disease have limited impact on disease progression and provide minimal relief from symptoms, and identifying treatments for this highly debilitating and costly disease is essential to healthcare in the 21st century. This study will identify the mechanisms by which a commonly occurring variant of the PERK gene may contribute to the development of Alzheimer?s Disease, with the aim of identifying genetic risk factors which may contribute to neurodegenerative processes in Alzheimer?s disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Joseph, Jeymohan
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University of Pennsylvania
Schools of Dentistry/Oral Hygn
United States
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Stern, Anna L; Lee, Rebecca N; Panvelker, Nina et al. (2018) Differential Effects of Antiretroviral Drugs on Neurons In Vitro: Roles for Oxidative Stress and Integrated Stress Response. J Neuroimmune Pharmacol 13:64-76
Stern, Anna L; Ghura, Shivesh; Gannon, Patrick J et al. (2018) BACE1 Mediates HIV-Associated and Excitotoxic Neuronal Damage Through an APP-Dependent Mechanism. J Neurosci 38:4288-4300
Gannon, Patrick J; Akay-Espinoza, Cagla; Yee, Alan C et al. (2017) HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ?-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. Am J Pathol 187:91-109