By 2050 older people at risk for cognitive decline and Alzheimer's (AD) are predicted to reach 13 million and health care costs are borne by individuals, their families, and society at large. Cholinergic dysfunction Is a main stay of AD and cholinesterase Inhibitor drug remain the mainstay for the management of mild to moderate AD. Our goal is to elucidate the earliest molecular and cellular events underlying the selective neuronal vulnerability ofthe cholinergic basal forebrain (CBF) memory connectome during the preclinical stage ofthe disease. Accomplishing this goal will be crucial for the development of novel disease modifying therapeutics for AD. In AD, the magnitude of cholinergic neuron and volume loss within the CBF subfields displays a rostrocaudal variation with the greatest cells loss in Its caudal subfield, which projects mainly to medial temporal cortex followed by its intermediate subfield, which projects to the lateral parietal lobule, and then to the rostral subfield, the least affected region, which innervates the frontal cortex. This suggests a circuit-based spatiotemporal course of CBF degeneration, which occurs in a caudal to rostral progression. CBF degeneration is not only manifested by specific post-translational modifications related to tau, but by a confluence of intracellular events related to endosomal-lysosomal (E-L) dysfunction and aberrant epigenetic events begin during preclinical AD. Data from the current grant revealed that select E-L gene products are upregulated in anterior cholinergic neurons along with their respective protein levels in MCI. We now report that neuronal E-L dysregulatlon progresses from the caudal to the rostral cholinergic subfields In MCI and In preclinical AD NCI. Accumulating data also implicate epigenetic factors in regulating lysosomal gene transcription and function In AD yet whether epigenetic changes effect E-L expression early in the disease remains unknown. We will apply site-specific tau, E-L and epigenetic antibodies and single cell array technology to the CBF subfields from preclinical AD and MCI cases. The subproject is well positioned to lay the groundwork for a wide range of potential Interventions that are truly distinct from approaches currently under investigation and may suggest novel biomarkers for the early diagnosis of dementia.
Cognitive decline 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 Impact our aging population.
|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|
|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|
|Counts, Scott E; Ray, Balmiki; Mufson, Elliott J et al. (2014) Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease. J Clin Immunol 34 Suppl 1:S80-5|
|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|
|Hales, Chadwick M; Dammer, Eric B; Diner, Ian et al. (2014) Aggregates of small nuclear ribonucleic acids (snRNAs) in Alzheimer's disease. Brain Pathol 24:344-51|
|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|
|Hales, Chadwick M; Seyfried, Nicholas T; Dammer, Eric B et al. (2014) U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer's disease due to autosomal dominant genetic mutations and trisomy 21. Mol Neurodegener 9:15|
|James, Bryan D; Leurgans, Sue E; Hebert, Liesi E et al. (2014) Contribution of Alzheimer disease to mortality in the United States. Neurology 82:1045-50|
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