The goal of this project is to use quantitative neuropathologic methods to define mild cognitive impairment (MCI) in the elderly and its relationship to Alzheimer's disease (AD). The focus is on a select group of markers for different stages of a pathogenetic sequence that we hypothesize begins with deposition of amino-terminally modified or truncated AB followed by deposition of full-length Ap that leads to neuroinflammation and subsequent cellular stress that manifests in aberrant activation of the cell cycle and cytoskeletal pathology in neurons and eventual synaptic loss. We hypothesize that biochemical alterations are widespread in the brain and not only in areas with obvious structural changes. We also hypothesize that there may be regional differences with respect to significant synaptic loss. Previously, we analyzed frontal lobe, but we will analyze cortical areas theoretically more (temporal) or less (occipital) vulnerable than the frontal lobe.
The specific aims are: 1) To analyze amyloid peptide heterogeneity using assays for amino-terminal modifications or truncation as well as full length A-beta, which we hypothesize deposits first as A-beta-1-42 and later as A-beta-l-40; 2) To analyze markers of neuroinflammation and astrocytosis, which we hypothesize is due to the changing nature of amyloid in the brain, by measuring microglial activation (HLA-DR and IL1a), astrocytic gliosis (GFAP) and proinflammatory cytokines (IL-l-beta, TNF-alpha, IL-6 and IL-1ra.); 3) To analyze cytoskeletal changes that we hypothesize may be the product of aberrant activation of the cell cycle due to cellular stress due to amyloid or neuroinflammation by extending tau assays to include assays for cyclin-dependent kinase-2 and downstream effects of cell cycle activation, specifically, markers of apoptosis (activated caspase-3 and caspase-3-cleaved fodrin); 4) To analyze markers indicative of neuronal structure and number, including synaptic markers (synaptophysin, SNAP25 and synuclein), NeuN and alpha-internexin; and finally, 5) To complete studies on age-related changes in white matter that may be structural correlates of cognitive and motor slowing in normal aging with immunoassays and immunocytochemistry for ubiquitin and myelin basic protein on additional normal elderly cases. The data will be analyzed across all diagnostic categories and clinical parameters to validate the proposed pathogenetic cascade. A profile of individual MCI cases will also be analyzed and compared to the average values of normals and AD to address the issue of heterogeneity of MCI and specifically to define an MCI phenotype that most closely resembles AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG014449-06
Application #
6481373
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (J2))
Project Start
1997-09-01
Project End
2007-03-31
Budget Start
Budget End
Support Year
6
Fiscal Year
2002
Total Cost
$133,835
Indirect Cost
Name
Mayo Clinic, Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
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
Mufson, Elliott J; He, Bin; Ginsberg, Stephen D et al. (2018) Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study. J Neurotrauma 35:1260-1271
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
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

Showing the most recent 10 out of 293 publications