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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Perez, Sylvia E; He, Bin; Nadeem, Muhammad et al. (2015) Resilience of precuneus neurotrophic signaling pathways despite amyloid pathology in prodromal Alzheimer's disease. Biol Psychiatry 77:693-703
Alldred, Melissa J; Lee, Sang Han; Petkova, Eva et al. (2015) Expression profile analysis of vulnerable CA1 pyramidal neurons in young-Middle-Aged Ts65Dn mice. J Comp Neurol 523:61-74
Alldred, Melissa J; Lee, Sang Han; Petkova, Eva et al. (2015) Expression profile analysis of hippocampal CA1 pyramidal neurons in aged Ts65Dn mice, a model of Down syndrome (DS) and Alzheimer's disease (AD). Brain Struct Funct 220:2983-96
Pivtoraiko, Violetta N; Abrahamson, Eric E; Leurgans, Sue E et al. (2015) Cortical pyroglutamate amyloid-? levels and cognitive decline in Alzheimer's disease. Neurobiol Aging 36:9-Dec
Mufson, Elliott J; Ward, Sarah; Binder, Lester (2014) Prefibrillar tau oligomers in mild cognitive impairment and Alzheimer's disease. Neurodegener Dis 13:151-3
Kelley, Christy M; Powers, Brian E; Velazquez, Ramon et al. (2014) Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice. J Comp Neurol 522:1390-410
Counts, Scott E; Alldred, Melissa J; Che, Shaoli et al. (2014) Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology 79:172-9
Ash, Jessica A; Velazquez, Ramon; Kelley, Christy M et al. (2014) Maternal choline supplementation improves spatial mapping and increases basal forebrain cholinergic neuron number and size in aged Ts65Dn mice. Neurobiol Dis 70:32-42
Yan, Jian; Ginsberg, Stephen D; Powers, Brian et al. (2014) Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice. FASEB J 28:4312-23