Alzheimer’s-specific Brain Amyloid Interactome: Neural-network Analysis of Intra-Aggregate Crosslinking Identifies Novel Drug Targets
ISCIENCE(2024)
Univ Arkansas Med Sci
Abstract
Alzheimer ' s disease (AD) is characterized by peri-neuronal amyloid plaque and intra-neuronal neurofibrillary tangles. These aggregates are identified by the immunodetection of '' seed '' proteins (A beta(1-42) and hyperphosphorylated tau, respectively), but include many other proteins incorporated nonrandomly. Using click-chemistry intra-aggregate crosslinking, we previously modeled amyloid '' contactomes '' in SY5Y-APP(Sw) neuroblastoma cells, revealing that aspirin impedes aggregate growth and complexity. By an analogous strategy, we now construct amyloid-specific aggregate interactomes of AD and age matched-control hippocampi. Comparing these interactomes reveals AD-specific interactions, from which neural-network (NN) analyses predict proteins with the highest impact on pathogenic aggregate formation and/or stability. RNAi knockdowns of implicated proteins, in C. elegans and human-cell-culture models of AD, validated those predictions. Gene-Ontology meta-analysis of AD-enriched influential proteins highlighted the involvement of mitochondrial and cytoplasmic compartments in AD-specific aggregation. This approach derives dynamic consensus models of aggregate growth and architecture, implicating highly influential proteins as new targets to disrupt amyloid accrual in the AD brain.
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Key words
Analytical chemistry,Biochemistry,Neuroscience
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