Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease

Crist, Angela M.; Hinkle, Kelly M.; Wang, Xue; Moloney, Christina M.; Matchett, Billie J.; Labuzan, Sydney A.; Frankenhauser, Isabelle; Azu, Nkem O.; Liesinger, Amanda M.; Lesser, Elizabeth R.; Serie, Daniel J.; Quicksall, Zachary; Patel, Tulsi; Carnwath, Troy; DeTure, Michael; Tang, Xiaojia; Petersen, Ronald C.; Duara, Ranjan; Graff‐Radford, Neill R.; Allen, Mariet; Carrasquillo, Minerva M.; Li, Hu; Ross, Owen A.; Ertekin-Taner, Nilüfer; Dickson, Dennis W.; Asmann, Yan W.; Carter, Rickey E.; Murray, Melissa E.

doi:10.1038/s41467-021-22399-3

Cited by 58 publications

(47 citation statements)

References 99 publications

(95 reference statements)

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“…However, when we removed three AD cases with RIN < 5 from our analyses and matched groups by RIN, three out of five genes investigated still displayed significant correlations when normalized to RPL30 . 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 ).…”

Section: Discussionsupporting

confidence: 91%

“…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 ).…”

Section: Discussionsupporting

confidence: 91%

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

Highet

Parker

Faull

et al. 2021

Front. Mol. Neurosci.

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Gene expression studies of human post-mortem brain tissue are useful for understanding the pathogenesis of neurodegenerative disease. These studies rely on the assumption that RNA quality is consistent between disease and neurologically normal cases; however, previous studies have suggested that RNA quality may be affected by neurodegenerative disease. Here, we compared RNA quality in human post-mortem brain tissue between neurologically normal cases (n = 14) and neurodegenerative disease cases (Alzheimer’s disease n = 10; Parkinson’s disease n = 11; and Huntington’s disease n = 9) in regions affected by pathology and regions that are relatively devoid of pathology. We identified a statistically significant decrease in RNA integrity number (RIN) in Alzheimer’s disease tissue relative to neurologically normal tissue (mixed effects model, p = 0.04). There were no statistically significant differences between neurologically normal cases and Parkinson’s disease or Huntington’s disease cases. Next, we investigated whether total RNA quality affected mRNA quantification, by correlating RIN with qPCR threshold cycle (CT). CT values for all six genes investigated were strongly correlated with RIN (p < 0.05, Pearson correlation); this effect was only partially mitigated by normalization to RPL30. Our results indicate that RNA quality is decreased in Alzheimer’s disease tissue. We recommend that RIN should be considered when this tissue is used in gene expression analyses.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

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

Highet

Parker

Faull

et al. 2021

Front. Mol. Neurosci.

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“…Transcriptome analysis of the postmortem human brain tissue 28 – 32 or genetically modified animal models 33 – 38 has provided a comprehensive overview of the transcriptional responses associated with AD pathogenesis. In particular, AICD has been proposed as a key epigenetic regulator of gene expression controlling a diverse range of genes.…”

Section: Discussionmentioning

confidence: 99%

Regulation of gene expression by the APP family in the adult cerebral cortex

Shen

Kang

2022

Sci Rep

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Amyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer’s disease. APP has two homologs, amyloid precursor-like protein 1 and 2 (APLP1 and APLP2), and they have functional redundancy. APP intracellular c-terminal domain (AICD), produced by sequential α- or β- and γ-secretase cleavages, is thought to control gene expression, similarly as the ICD of Notch. To investigate the role of APP family in transcriptional regulation, we examined gene expression changes in the cerebral cortex of APP/APLP1/APLP2 conditional triple knockout (cTKO) mice, in which APP family members are selectively inactivated in excitatory neurons of the postnatal forebrain. Of the 12 previously reported AICD target genes, only Nep and Npas4 mRNA levels were significantly reduced in the cerebral cortex of cTKO mice, compared to littermate controls. We further examined global transcriptional changes by RNA-seq and identified 189 and 274 differentially expressed genes in the neocortex and hippocampus, respectively, of cTKO mice relative to controls. Gene Ontology analysis indicated that these genes are involved in a variety of cellular functions, including extracellular organization, learning and memory, and ion channels. Thus, inactivation of APP family alters transcriptional profiles of the cerebral cortex and affects wide-ranging molecular pathways.

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“…The atrophy of the hippocampus, essential for memory formation and consolidation [ 9 , 13 , 49 ], is associated with memory impairment in normal ageing [ 34 ] and is predictive of Alzheimer’s disease (AD) and associated dementia [ 3 , 26 ]. The hippocampus is one of the most severely affected brain regions in AD and dementia with Lewy Bodies (DLB) [ 4 , 20 , 28 , 64 ] but the causes of its vulnerability are still poorly understood. The hippocampal architecture has been widely studied for its tri-synaptic loop circuitry and its composition in five distinct subfields, the dentate gyrus (DG), as well as the four Cornu ammonis (CA) fields [ 8 ] dedicated to specific types or sequences of memory processes [ 18 , 82 , 94 ].…”

Section: Introductionmentioning

confidence: 99%

Microglia phenotypes are associated with subregional patterns of concomitant tau, amyloid-β and α-synuclein pathologies in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies

Fixemer

Ameli

Hammer

et al. 2022

acta neuropathol commun

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The cellular alterations of the hippocampus lead to memory decline, a shared symptom between Alzheimer’s disease (AD) and dementia with Lewy Bodies (DLB) patients. However, the subregional deterioration pattern of the hippocampus differs between AD and DLB with the CA1 subfield being more severely affected in AD. The activation of microglia, the brain immune cells, could play a role in its selective volume loss. How subregional microglia populations vary within AD or DLB and across these conditions remains poorly understood. Furthermore, how the nature of the hippocampal local pathological imprint is associated with microglia responses needs to be elucidated. To this purpose, we employed an automated pipeline for analysis of 3D confocal microscopy images to assess CA1, CA3 and DG/CA4 subfields microglia responses in post-mortem hippocampal samples from late-onset AD (n = 10), DLB (n = 8) and age-matched control (CTL) (n = 11) individuals. In parallel, we performed volumetric analyses of hyperphosphorylated tau (pTau), amyloid-β (Aβ) and phosphorylated α-synuclein (pSyn) loads. For each of the 32,447 extracted microglia, 16 morphological features were measured to classify them into seven distinct morphological clusters. Our results show similar alterations of microglial morphological features and clusters in AD and DLB, but with more prominent changes in AD. We identified two distinct microglia clusters enriched in disease conditions and particularly increased in CA1 and DG/CA4 of AD and CA3 of DLB. Our study confirms frequent concomitance of pTau, Aβ and pSyn loads across AD and DLB but reveals a specific subregional pattern for each type of pathology, along with a generally increased severity in AD. Furthermore, pTau and pSyn loads were highly correlated across subregions and conditions. We uncovered tight associations between microglial changes and the subfield pathological imprint. Our findings suggest that combinations and severity of subregional pTau, Aβ and pSyn pathologies transform local microglia phenotypic composition in the hippocampus. The high burdens of pTau and pSyn associated with increased microglial alterations could be a factor in CA1 vulnerability in AD.

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Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease

Cited by 58 publications

References 99 publications

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

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

Regulation of gene expression by the APP family in the adult cerebral cortex

Microglia phenotypes are associated with subregional patterns of concomitant tau, amyloid-β and α-synuclein pathologies in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies

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