CORE--NEUROPATHOLOGY

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

Alzheimer's (AD) and Parkinson's disease (PD) are characterized by distinct clinical and neuropathological abnormalities. However, an AD- like dementia emerges in many PD patients and PD-like extrapyramidal signs are common in AD. Neurofibrillary tangles (NFTs) and senile plaques (SPs) are hallmark brain lesions of AD and Lewy bodies (Lbs) are neuropathological signatures of PD, but abundant NFTs and SPs als occur in brains of demented PD patients and AD brains frequently contain many cortical and subcortical Lbs. The reasons for this are enigmatic but may reflect similarities in the neurodegenerative mechanisms underlying these disorders. Now, new opportunities to investigate this possibility have emerged from advances in understanding the molecular neuropathology of PD and AD since the initial identification of the non- amyloid component (NAC) of AD amyloid plaques and recognition and recognition that the NAC precursor protein (NACAP) is alpha-synuclein (AS). Specifically, it is now known that: 1) Mutations in the AS gene cause familial PD, 2) Wild type AS forms LB-like filaments and as a major component of Lbs in PD, the LB variants of AD (LBVAD) and dementia with LBs (DLB), 3) AS positive Lbs occur in >60% of familial AD brains and >50% of Down's syndrome brains with AD, and 4) glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA) are formed by AS filaments. Moreover, we recently detected novel dystrophic processes in the hippocampus of PD and DLB brains with antibodies to beta- (BS) and gamma-synucleins (GS). Thus, all 3 of these synucleins may be implicated in the brain degeneration of PD, AD and related disorders. For these reasons, Project 1-4 in this Program Project propose complementary strategies to elucidate the role synuclein pathology plays in the onset-progression of AD, PD and related neurodegenerative diseases characterized by synuclein lesions. Thus, the goal of Core C is to support the research pursued in these Projects by obtaining and characterizing postmortem brains from controls and patients with PD, AD, LBVAD, DLB, MSA or related disorders, and providing samples from these brains to investigators in Projects 1-4. Additionally, Core C will monitor potential risk factor alleles for synucleinopathies in Program Project subprojects, and provide advice as well as technical support to investigators in all 4 Projects using human brain tissues in their research.