Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

Abstract

Tau pathology in Alzheimer’s disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The ‘early’ AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

RNA Quality in Post-mortem Human Brain Tissue Is Affected by Alzheimer’s Disease

“…This result corroborates a recent RNA-seq study which found that RIN affected differential gene expression analysis of AD HP tissue compared to normal HP tissue even with a RIN cut-off of 7 ( Crist et al, 2021 ). Thus, this study and others have recommended that RIN is included as a co-variate during statistical analyses ( Crist et al, 2021 ; Guennewig et al, 2021 ).…”

Key Genes and Biochemical Networks in Various Brain Regions Affected in Alzheimer’s Disease

“…However, data from the other regions, especially those that are less affected by AD such as the cerebellum, are not well-studied and are sometimes even excluded from meta-analyses [15,16]. Exploring these changes in less affected brain regions may open new avenues to enhance the molecular understanding of AD pathogenesis and may reveal key disease mechanism in affected brain regions [17]. Therefore, in this study we have combined multiple gene expression datasets from five brain regions including the hippocampus, cerebellum, frontal, entorhinal and temporal cortices of AD patients and healthy controls, and used robust rank aggregation (RRA) meta-analysis to find robust differentially expressed genes (DEGs) between AD cases and healthy controls.…”

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

“…It is characterised by the progressive loss of memory and neuropsychiatric symptoms, resulting from loss of cortical neurons (located in the locus coeruleus and nucleus basalis of Meynert) in the brain [ 150 , 151 ]. Several mechanisms are implicated in the pathophysiology of Alzheimer’s disease, including Aβ deposition [ 152 ], tau hyperphosphorylation [ 152 ], neuroinflammation [ 150 ], constriction of brain capillaries [ 153 ], Aβ interaction with hippocampal ghrelin/GHSR1α signalling [ 154 ], DNA damage [ 155 ], disrupted RNA hemostasias [ 156 ], mitochondrial dysfunction [ 157 ], endoplasmic reticulum (ER) stress [ 158 ], and proteostasis dysfunction [ 159 ]. The pathological hallmarks of AD [ 160 ] are deposition of extracellular Aβ plaques and intracellular neurofibrillary tangles (NFTs).…”