Alzheimer's-specific brain amyloid interactome: Neural-network analysis of intra-aggregate crosslinking identifies novel drug targets

Meenakshisundaram Balasubramaniam; Akshatha Ganne; Nirjal Mainali; Sonu Pahal; Srinivas Ayyadevara; Robert J Shmookler Reis

doi:10.1016/j.isci.2023.108745

Alzheimer's-specific brain amyloid interactome: Neural-network analysis of intra-aggregate crosslinking identifies novel drug targets

iScience. 2023 Dec 18;27(1):108745. doi: 10.1016/j.isci.2023.108745. eCollection 2024 Jan 19.

Authors

Meenakshisundaram Balasubramaniam¹, Akshatha Ganne¹, Nirjal Mainali², Sonu Pahal², Srinivas Ayyadevara^{1

3}, Robert J Shmookler Reis^{1

3}

Affiliations

¹ Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
² Bioinformatics Program, University of Arkansas for Medical Sciences and University of Arkansas at Little Rock, Little Rock, AR 72205, USA.
³ McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA.

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 (Aβ_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.

Keywords: Analytical chemistry; Biochemistry; Neuroscience.

Abstract

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