Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis

Abstract

A major obstacle to treating Alzheimer's disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, which is a key characteristic of the disease. Here we present a framework to integrate highquality neuron-type specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for AD vulnerable and resistant neurons, identify specific genes and pathways associated with AD pathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by both amyloid accumulation and aging. Overall, our study provides a molecular framework for understanding the complex interplay between Aβ, aging, and neurodegeneration within the most vulnerable neurons in AD.

Single-cell anatomical analysis of human hippocampus and entorhinal cortex uncovers early-stage molecular pathology in Alzheimer’s disease

“…Patterns of alteration in glutamatergic neurons reveal an anatomical pattern of neuronal impact across human hippocampal substructures, with CA1 pyramidal neurons most affected, followed by pyramidal neurons of entorhinal deep and mid layers, and ending up with CA3 neurons and DG granule cells which show the least effect. These observations are consistent with the selective vulnerability of CA1 and EC pyramidal cells 11,21,39 , and suggest that observed transcriptomic responses may reflect molecular processes relevant for neuronal dysfunction. Potentially among the latter, we found that CA1 neurons show simultaneous downregulation of homeostatic neuronal functions and upregulation of processes suggestive of neuronal stress, including metabolic alterations, cytoskeletal transport dysfunction, inflammatory responses, and genes involved in neurodegeneration.…”

“…We next sought to pinpoint specific anatomical structures and neuronal subtypes where AD-associated changes preferentially occur, by quantifying the association between gene expression levels and neurofibrillary tangle pathology (NFT) burden for each neuronal subtype separately ( Supplementary Table S9 ). Given the intracellular and selective character of NFT pathology 22 , we used a targeted approach to uncover molecular processes potentially mediating neuronal dysfunction, specifically focusing on anatomical structures and neuronal populations that are robustly annotated, directly targeted during tissue recollection, and expected to include neurons that are vulnerable to neurodegeneration 21,39 . For glutamatergic neurons, we focused on CA1, CA3, and DG subtypes from the hippocampus ( Fig.…”

The proto-oncogene DEK regulates neuronal excitability and tau accumulation in Alzheimer’s disease vulnerable neurons

“…Cell-type specific profiling technologies have made it possible to characterize their gene expression profiles, but how genes operate in the specific context of these cells and how they are related to disease cannot be readily parsed out by mere profiling. We recently used high quality molecular signatures of ECII neurons along with a large compendium of genomics data to build maps of functional gene interactions within the context of ECII neurons (Roussarie et al, 2020). Contrasting ECII neurons with neurons more resistant to AD, we found that pathways related to microtubule remodeling were particularly salient in ECII neurons.…”

“…Contrasting ECII neurons with neurons more resistant to AD, we found that pathways related to microtubule remodeling were particularly salient in ECII neurons. To investigate AD processes in the specific context of ECII neurons we used our NetWAS 2.0 (Network-Wide Association Study 2.0) algorithm, which leveraged our ECII functional map along with genome wide association study data for NFT formation (Beecham et al, 2014; Roussarie et al, 2020). NetWAS 2.0 re-prioritized genes based on their association with tau pathology within vulnerable neurons.…”

“…Out of these 4 modules, one displayed higher connectivity in ECII neurons than in any other neuron type, thus it might represent a cellular process that is more central in ECII neurons than in other neurons. Furthermore, this module, enriched in genes involved in axonal plasticity, was affected by aging and amyloid pathology (Roussarie et al, 2020). While these results suggest that alterations in this module could underlie tau pathology in AD vulnerable neurons, details of its regulation, and its relevance for physiological and pathological mechanisms remain to be understood.…”