Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology

Dehkordi, Shiva Kazempour; Walker, Jamie M.; Sah, Eric; Bennett, Emma; Atrian, Farzaneh; Frost, Bess; Woost, Benjamin; Bennett, Rachel E.; Orr, Timothy C; Zhou, Yingyue; Andhey, Prabhakar S.; Colonna, Marco; Sudmant, Peter H.; Xu, Peng; Wang, Minghui; Zhang, Bin; Zare, Habil; Orr, Miranda E.

doi:10.1038/s43587-021-00142-3

Cited by 65 publications

(70 citation statements)

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“…Other notable differentially expressed proteins included Histone H3 and Ki-67. Their expression patterns in NFT-bearing neurons (lower and higher, respectively) is consistent with chromatin remodeling and potential exit from quiescence [ 40 ] which have been linked to pathogenic tau accumulation [ 18 ] and senescence [ 13 , 37 ]. We also found elevated TDP-43 and ubiquitin in NFT-bearing neurons.…”

Section: Resultsmentioning

confidence: 66%

“…Previous studies have examined transcriptomic gene expression changes within neurofibrillary tangles [ 13 , 16 , 29 ] and in AD brains [ 29 ], however many of the genes that are upregulated do not correlate well with protein expression changes. In the prefrontal cortex, GFAP gene expression was found to be upregulated in AD brains [ 29 ], and in CA1 pyramidal neurons gene expression of synaptophysin and PSD-95 were downregulated in individuals with MCI and AD [ 12 ], corroborating our findings of preservation of synaptophysin and PSD-95 protein expression in the resilient hippocampi.…”

Section: Discussionmentioning

confidence: 99%

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Differential protein expression in the hippocampi of resilient individuals identified by digital spatial profiling

Walker

Dehkordi²,

Fracassi³

et al. 2022

acta neuropathol commun

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Clinical symptoms correlate with underlying neurodegenerative changes in the vast majority of people. However, an intriguing group of individuals demonstrate neuropathologic changes consistent with Alzheimer disease (AD) yet remain cognitively normal (termed “resilient”). Previous studies have reported less overall neuronal loss, less gliosis, and fewer comorbidities in these individuals. Herein, NanoString GeoMx™ Digital Spatial Profiler (DSP) technology was utilized to investigate protein expression differences comparing individuals with dementia and AD neuropathologic change to resilient individuals. DSP allows for spatial analysis of protein expression in multiple regions of interest (ROIs) on formalin-fixed paraffin-embedded sections. ROIs in this analysis were hippocampal neurofibrillary tangle (NFT)-bearing neurons, non-NFT-bearing neurons, and their immediate neuronal microenvironments. Analyses of 86 proteins associated with CNS cell-typing or known neurodegenerative changes in 168 ROIs from 14 individuals identified 11 proteins displaying differential expression in NFT-bearing neurons of the resilient when compared to the demented (including APP, IDH1, CD68, GFAP, SYP and Histone H3). In addition, IDH1, CD68, and SYP were differentially expressed in the environment of NFT-bearing neurons when comparing resilient to demented. IDH1 (which is upregulated under energetic and oxidative stress) and PINK1 (which is upregulated in response to mitochondrial dysfunction and oxidative stress) both displayed lower expression in the environment of NFT-bearing neurons in the resilient. Therefore, the resilient display less evidence of energetic and oxidative stress. Synaptophysin (SYP) was increased in the resilient, which likely indicates better maintenance of synapses and synaptic connections. Furthermore, neurofilament light chain (NEFL) and ubiquitin c-terminal hydrolase (Park5) were higher in the resilient in the environment of NFTs. These differences all suggest healthier intact axons, dendrites and synapses in the resilient. In conclusion, resilient individuals display protein expression patterns suggestive of an environment containing less energetic and oxidative stress, which in turn results in maintenance of neurons and their synaptic connections.

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Section: Resultsmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Differential protein expression in the hippocampi of resilient individuals identified by digital spatial profiling

Walker

Dehkordi²,

Fracassi³

et al. 2022

acta neuropathol commun

Self Cite

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“…Rodent studies have demonstrated senescent cell accumulation in the brain in response to accumulation of tau ( 90 , 97 ) or Aβ protein ( 98 ); dysfunctional immune system ( 96 ); high-fat diet or obesity ( 99 ); insulin resistance ( 100 ); chronic unpredictable stress ( 101 ); environmental neurotoxins ( 102 ); and brain injury ( 103 ). Studies using postmortem human brain tissue have identified multiple senescent cell types in AD, including astrocytes ( 104 ), neurons ( 90 , 105 ), microglia ( 106 ), oligodendrocyte precursor cells ( 98 ), and endothelial cells ( 107 ). Unbiased single-cell transcriptomics on dorsolateral prefrontal cortex from human AD revealed excitatory neurons as a prominent senescent cell type driven by CDKN2D (encoding p19) that overlapped with neurons bearing neurofibrillary tangles (NFTs) ( 105 ).…”

Section: Biological Aging Hallmarks Of Cognitive Decline and Adrdmentioning

confidence: 99%

“…Studies using postmortem human brain tissue have identified multiple senescent cell types in AD, including astrocytes ( 104 ), neurons ( 90 , 105 ), microglia ( 106 ), oligodendrocyte precursor cells ( 98 ), and endothelial cells ( 107 ). Unbiased single-cell transcriptomics on dorsolateral prefrontal cortex from human AD revealed excitatory neurons as a prominent senescent cell type driven by CDKN2D (encoding p19) that overlapped with neurons bearing neurofibrillary tangles (NFTs) ( 105 ). In contrast, bioinformatics analyses of data derived from bulk tissue from healthy human tissue donors revealed that prominent senescent cell types in the brain included endothelial cells and microglia driven by CDKN1A ( 108 ).…”

Section: Biological Aging Hallmarks Of Cognitive Decline and Adrdmentioning

confidence: 99%

“…Microglia, the macrophage-like cells of the brain, clear NFT-bearing neurons that display phosphatidylserine on their surface ( 109 ). Given that microglia become senescent and dysfunctional after clearing these possibly senescent, NFT-bearing neurons ( 105 ), therapeutic strategies to help remove senescent cells from the brain may alleviate senescent cell burden, inflammation, and disease propagation ( 90 , 98 ). Clinical trials are currently under way to test this approach ( 110 , 111 ).…”

Section: Biological Aging Hallmarks Of Cognitive Decline and Adrdmentioning

confidence: 99%

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Biological aging processes underlying cognitive decline and neurodegenerative disease

Gonzales

Garbarino

Pollet

et al. 2022

Journal of Clinical Investigation

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119

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Alzheimer’s disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. As with many chronic conditions, aging is the single most influential factor in the development of ADRD. Even among older adults who remain free of dementia throughout their lives, cognitive decline and neurodegenerative changes are appreciable with advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview of changes in cognition, brain morphology, and neuropathological protein accumulation across the lifespan in humans, with complementary and mechanistic evidence from animal models. Next, we highlight selected aging processes that are differentially regulated in neurodegenerative disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular dysfunction, inflammation, and lipid dysregulation. We summarize research across clinical and translational studies to link biological aging processes to underlying ADRD pathogenesis. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. Collaboration across the fields of geroscience and neuroscience, coupled with the development of new translational animal models that more closely align with human disease processes, is necessary to advance novel therapeutic discovery in this realm.

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Distinct transcriptomic responses to Aβ plaques, neurofibrillary tangles, and APOE in Alzheimer's disease

Das

Wachter

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONOmics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer's disease (AD) but the spatial relationships with plaques and tangles and APOE‐linked differences remain unclear.METHODSWe performed laser capture microdissection of amyloid beta (Aβ) plaques, the 50 μm halo around them, tangles with the 50 μm halo around them, and areas distant (> 50 μm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA‐sequencing.RESULTSAβ plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Aβ plaques had more differentially expressed genes than tangles. We identified a gradient Aβ plaque > peri‐plaque > tangle > distant for these changes. AD APOE ε4 homozygotes had greater changes than APOE ε3 across locations, especially within Aβ plaques.DISCUSSIONTranscriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Aβ plaques, and are exacerbated by the APOE ε4 allele.

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Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology

Cited by 65 publications

References 54 publications

Differential protein expression in the hippocampi of resilient individuals identified by digital spatial profiling

Differential protein expression in the hippocampi of resilient individuals identified by digital spatial profiling

Biological aging processes underlying cognitive decline and neurodegenerative disease

Distinct transcriptomic responses to Aβ plaques, neurofibrillary tangles, and APOE in Alzheimer's disease

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