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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
St. Joseph's Hospital and Medical Center
United States
Zip Code
Kelly, Sarah C; He, Bin; Perez, Sylvia E et al. (2017) Locus coeruleus cellular and molecular pathology during the progression of Alzheimer's disease. Acta Neuropathol Commun 5:8
McKay, Erin; Counts, Scott E (2017) Multi-Infarct Dementia: A Historical Perspective. Dement Geriatr Cogn Dis Extra 7:160-171
Perez, Sylvia E; Nadeem, Muhammad; Malek-Ahmadi, Michael H et al. (2017) Frontal Cortex and Hippocampal ?-Secretase Activating Protein Levels in Prodromal Alzheimer Disease. Neurodegener Dis 17:235-241
Marquié, Marta; Normandin, Marc D; Meltzer, Avery C et al. (2017) Pathological correlations of [F-18]-AV-1451 imaging in non-alzheimer tauopathies. Ann Neurol 81:117-128
Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E (2017) Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders. Ageing Res Rev 34:51-63
Krivinko, Josh M; Erickson, Susan L; Abrahamson, Eric E et al. (2017) Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice. Neurobiol Aging 54:59-70
Sorrentino, Vincenzo; Romani, Mario; Mouchiroud, Laurent et al. (2017) Enhancing mitochondrial proteostasis reduces amyloid-? proteotoxicity. Nature 552:187-193
Mahady, Laura J; Perez, Sylvia E; Emerich, Dwaine F et al. (2017) Cholinergic profiles in the Goettingen miniature pig (Sus scrofa domesticus) brain. J Comp Neurol 525:553-573
Counts, Scott E; Mufson, Elliott J (2017) Regulator of Cell Cycle (RGCC) Expression During the Progression of Alzheimer's Disease. Cell Transplant 26:693-702
Powers, Brian E; Kelley, Christy M; Velazquez, Ramon et al. (2017) Maternal choline supplementation in a mouse model of Down syndrome: Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring. Neuroscience 340:501-514

Showing the most recent 10 out of 270 publications