This project will examine the relation of oligomeric and fibrillar amyloid-p (AP) species with changes in postsynaptic dendritic spines and pre-synaptic axonal terminals within the cortical default mode network (DMN) over the clinical progression of Alzheimer's disease (AD). To gain greater insight into the structural basis of functional deficits and how they relate to amyloid pathology in these regions, we propose to quantify AB and synaptic changes in postmortem brain tissues from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), or early AD. We will divide NCI subjects into low/no pathology (LP-NCl) and high pathology (HP-NCl) groups which are considered to be preclinical AD cases, to examine synaptic changes in the presence of AB at the earliest stages of the disease. AB analyses will target oligomeric AB in the synaptosomal compartment, and N-terminus truncated and pyroglutamate modified (NpE) AB. Spatial relation of synaptic markers with oligomeric and NpE AB deposits will be analyzed by confocal microscopy. To complete our proposed Aims, first we will quantify concentrations of oligomeric and NpE AB in whole tissue homogenate and synaptosome fraction from DMN regions (Aim 1). We will also correlate these changes with neuropathology (e.g. tau) of the cholinergic basal forebrain neurons which project to these cortical areas and are studies in subprojects 1 and 3.
In Aim 2, dendritic spine density will be quantified, by complementary analyses of a post-synaptic protein biochemical assay and confocal microscopy in tissue sections, and correlated with variables quantified in Aim 1.
Aim 3 will quantify cholinergic, glutamatergic, and GABAergic terminals in DMN regions to determine how they change relative to increased oligomeric AB in synaptosomes, NpE AB, PiB binding, and to changes in dendritic spines in HP-NCl, MCI, and AD. Elucidation ofthe histopathological and biochemical signatures of clinical transitions from preclinical to MCI to AD will guide development of novel diagnostic imaging and therapic agents.

Public Health Relevance

Alzheimer's disease is a major cause of dementia in the elderly, and currently there is no effective treatment. The proposed studies will examine subjects in the earliest stages of the disease and will shed new light on the role of amyloid pathology in the brain and its relation to a progressive impairment of neuronal communications and declining memory function in these people.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG014449-16
Application #
8619880
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
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
Jansen, Willemijn J; Wilson, Robert S; Visser, Pieter Jelle et al. (2018) Age and the association of dementia-related pathology with trajectories of cognitive decline. Neurobiol Aging 61:138-145
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
Krivinko, Josh M; Erickson, Susan L; Ding, Ying et al. (2018) Synaptic Proteome Compensation and Resilience to Psychosis in Alzheimer's Disease. Am J Psychiatry 175:999-1009
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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