Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

Abstract

Rapidly progressive Alzheimer’s disease (rpAD) is a particularly aggressive form of Alzheimer’s disease, with a median survival time of 7–10 months after diagnosis. Why these patients have such a rapid progression of Alzheimer’s disease is currently unknown. To further understand pathological differences between rpAD and typical sporadic Alzheimer’s disease (sAD) we used localized proteomics to analyze the protein differences in amyloid plaques in rpAD and sAD. Label-free quantitative LC-MS/MS was performed on amyloid plaques microdissected from rpAD and sAD patients (n=22 for each patient group) and protein expression differences were quantified. On average, 913±30 (mean±SEM) proteins were quantified in plaques from each patient and 279 of these proteins were consistently found in plaques from every patient. We found significant differences in protein composition between rpAD and sAD plaques. We found that rpAD plaques contained significantly higher levels of neuronal proteins (p=0.0017) and significantly lower levels of astrocyte proteins (p=1.08x10−6). Unexpectedly, cumulative protein differences in rpAD plaques did not suggest accelerated typical sAD. Plaques from patients with rpAD were particularly abundant in synaptic proteins, especially those involved in synaptic vesicle release, highlighting the potential importance of synaptic dysfunction in the accelerated development of plaque pathology in rpAD. Combined, our data provides new direct evidence that amyloid plaques do not all have the same protein composition and that the proteomic differences in plaques could provide important insight into the factors that contribute to plaque development. The cumulative protein differences in rpAD plaques suggest rpAD may be a novel subtype of Alzheimer’s disease.

Patterns of Expression of Purinergic Receptor P2RY12, a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer’s Disease Brains

“…With the use of laser capture microscopy and proteomics techniques, analyses of micro-dissected regions are feasible and could identify key neuroinflammatory factors associated with AD that are not represented when larger dissected pieces of brain tissue are analyzed. The feasibility of this approach has been demonstrated in proteomic analyses of micro-dissected plaques and tangles from AD brains [49,50]. microglial P2RY12 with ticagrelor, an antagonist, reduced ischemic damage by microglia by reducing their migration to sites of injury [47].…”

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

“…Promising studies in transgenic mouse models of amyloidosis are currently ongoing in our laboratory. The physiological relevance of this approach is further highlighted by recent proteomic studies showing increased CAII in the mitochondria in aging and neurodegeneration (Pollard et al., 2016), as well as by our group's recent findings demonstrating the presence of multiple CA enzymes in amyloid plaques within the AD human brain (Drummond et al., 2017). …”

Proteomics of neurodegenerative diseases: analysis of human post‐mortem brain

“…To better understand rpAD, Drummond and colleagues compared the proteomes of amyloid plaques isolated from 22 cases each of rpAD and sporadic AD (Drummond et al . ). The immunohistochemically stained plaques from formalin‐fixed paraffin‐embedded tissue blocks were selected and microdissected via LMD and about 740 plaques per sample were collected.…”