By 2050 older people at risk for cognitive decline are predicted to reach 13 million and health care costs are borne by individuals, their families, and society at large. The overall goal of the proposed project is determine the earliest cellular and molecular changes underlying the disconnection of the neuronal memory circuit within the medial temporal lobe (MTL), which degenerates in a highly predictable region-to-region pattern beginning prior to the onset of cognitive decline in the elderly. A growing literature implicated endosmal/lysosomal (E-L) dysfunction occur even before the formation of the classic pathologic AD lesion, the neurofibrillary tangle (NFT), composed of polymers of the microtubule-associated protein, tau. NFTs occur first in the transentorhinal cortex (TEC) then spread to the entorhinal cortex (EC) layer II and then to the hippocampal formation (HF) CA1 neurons of the MTL. Our group has shown that E-L rab GTPase genes are dysregulated in HPC CA1 neurons in MCI. Building on these findings, we propose to perform single cell expression profiling combined with site specific tau antibody neuronal labeling to test whether select rab GTPases are differentially regulated early during the evolution of TEC layer III NFTs prior to ether EC or HF prior to cognitive decline. We will examine whether select tau cytoskeletal isoforms and/or rab expression correlate with clinical diagnosis, memory tests specific to the MTL connectome, amyloid and apolipoprotein E genotype in preclinical AD. The project will characterize how pathology alters the neuronal environment at the mRNA expression level and provide new information on the complex mechanism(s) driving the molecular pathogenesis underlying MTL degeneration before clinical onset of dementia. This timely, novel and powerful approach will transform our understanding of the contributions of E-L expression to the vulnerability of MTL neurons in preclinical AD. The project is well positioned to lay the groundwork for a wide range of potential interventions that are truly distinct from approaches currently under investigation. I addition, the novel information gained about role that intraneuronal site-specific tau epitopes, E-L activation and amyloid pathology play in the vulnerability of MTL neurons may provide a panel of targets to better inform CSF tau based screening for dementia onset.

Public Health Relevance

Cognitive decline and dementia associated with AD represent a major public health problem. Disease prevention provides the best long-term strategy to reduce the human and economic toll of AD. This timely study of preclincial AD molecular and cellular pathobiology could provide new knowledge critical to the development of novel drug therapies for dementia as well as impact public health policy needed to make the crucial difference for our aging population.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Petanceska, Suzana
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Rush University Medical Center
Schools of Medicine
United States
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Mahady, Laura; Nadeem, Muhammad; Malek-Ahmadi, Michael et al. (2018) Frontal Cortex Epigenetic Dysregulation During the Progression of Alzheimer's Disease. J Alzheimers Dis 62:115-131
Alldred, Melissa J; Chao, Helen M; Lee, Sang Han et al. (2018) CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation. Hippocampus 28:251-268
Jeanneteau, Freddy; Barrère, Christian; Vos, Mariska et al. (2018) The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and Synapse Number in Prefrontal Cortex. J Neurosci 38:1335-1350
Mahady, L; Nadeem, M; Malek-Ahmadi, M et al. (2018) HDAC2 dysregulation in the nucleus basalis of Meynert during the progression of Alzheimer's disease. Neuropathol Appl Neurobiol :
Peng, Katherine Y; Pérez-González, Rocío; Alldred, Melissa J et al. (2018) Apolipoprotein E4 genotype compromises brain exosome production. Brain :
Ginsberg, Stephen D; Alldred, Melissa J; Gunnam, Satya M et al. (2018) Expression profiling suggests microglial impairment in human immunodeficiency virus neuropathogenesis. Ann Neurol 83:406-417
Tiernan, Chelsea T; Ginsberg, Stephen D; He, Bin et al. (2018) Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease. Neurobiol Dis 117:125-136
Kaur, Gurjinder; Gauthier, Sebastien A; Perez-Gonzalez, Rocio et al. (2018) Cystatin C prevents neuronal loss and behavioral deficits via the endosomal pathway in a mouse model of down syndrome. Neurobiol Dis 120:165-173
Tiernan, Chelsea T; Mufson, Elliott J; Kanaan, Nicholas M et al. (2018) Tau Oligomer Pathology in Nucleus Basalis Neurons During the Progression of Alzheimer Disease. J Neuropathol Exp Neurol 77:246-259
Malek-Ahmadi, Michael; Chen, Kewei; Perez, Sylvia E et al. (2018) Cognitive composite score association with Alzheimer's disease plaque and tangle pathology. Alzheimers Res Ther 10:90

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