Control of mammalian brain aging by the unfolded protein response (UPR)

Abstract

Aging is the major risk factor for the development of dementia and neurodegenerative disorders, and the aging brain manifests severe deficits in buffering capacity by the proteostasis network. Accordingly, we investigated the significance of the unfolded protein response (UPR), a major signaling pathway that copes with endoplasmic reticulum (ER) stress, to normal mammalian brain aging. Genetic disruption of ER stress sensor IRE1α accelerated cognitive and motor dysfunction during aging. Exogenous bolstering of the UPR by overexpressing an active form of the transcription factor XBP1 restored synaptic and cognitive function in addition to reducing cell senescence.Remarkably, proteomic profiling of hippocampal tissue indicated that XBP1s expression corrected age-related alterations in synaptic function. Collectively, our data demonstrate that strategies to manipulate the UPR sustain healthy brain aging.One Sentence Summary: The IRE1/XBP1 pathway dictates when and how brain function declines during aging. Main Text:Normal aging is associated with progressive cognitive impairment, representing the most prevalent risk factor for the development of dementia in neurodegenerative disorders. Subtle structural and functional alterations in synapses are the main drivers of age-related cognitive decline (reviewed in 1), but the molecular mechanisms dictating these perturbations are still elusive. Decades of research have defined the hallmarks of

Mastering organismal aging through the endoplasmic reticulum proteostasis network

“…These results are in conflict with the idea that the activity of the UPR, and more specifically the IRE1α/XBP1 branch, is attenuated during aging. However, experimental induction of ER stress with pharmacological agents has been shown to result in attenuated UPR signaling in the aging brain compared to young animals (Cabral‐Miranda et al, 2020). It might be possible that the inability to properly engage the UPR in the long‐term produces damage to ER physiology that is compensated for by the upregulation of proteostasis components (ER stress markers) through alternative regulatory pathways.…”

“…It has been reported that the genetic or pharmacological reduction of eIF2α phosphorylation or ATF4/PERK expression improves synaptic plasticity and the performance of animals in memory‐related tasks (reviewed in (Martinez et al, 2018)). Three studies available in the BioRxiv repository might provide the first direct evidence for an involvement of the UPR in normal brain aging (Cabral‐Miranda et al, 2020; Krukowski et al, 2020; Longo et al, 2020). Genetic depletion of PERK in dopaminergic neurons was shown to reduce dopamine release in the striatum on an age‐dependent manner, associated with progressive motor dysfunction (Longo et al, 2020).…”

“…Remarkably, the artificial expression of the active form of XBP1s in the brain using transgenic mice prevented age‐dependent decline of brain function. And, importantly, gene therapy to specifically deliver XBP1s into the hippocampus was able to revert the spontaneous decline of learning and memory capacity, thus restoring cognitive function in aged animals (Cabral‐Miranda et al, 2020).…”

Small molecule cognitive enhancer reverses age-related memory decline in mice

“…The principle that blocking protein synthesis prevents long-term memory storage was discovered many years ago (22). With age there is a marked decline of protein synthesis in the brain that correlates with defects in proper protein folding (12,(23)(24)(25).…”

“…Age-related decline in memory has been recapitulated in preclinical studies with old rodents ( Chou et al, 2018 ; Yousef et al, 2019 ; Villeda et al, 2011 ; Castellano et al, 2017 ). Specifically, prior studies have identified deficits in spatial memory ( Villeda et al, 2011 ; Villeda et al, 2014 ), working and episodic memory ( Yousef et al, 2019 ; Castellano et al, 2017 ) and recognition memory ( Cabral-Miranda et al, 2020 ), when comparing young, adult mice with older sex-matched animals. The hippocampus is the brain region associated with learning and memory formation and is particularly vulnerable to age-related changes in humans and rodents ( Disterhoft and Oh, 2007 ; McKiernan and Marrone, 2017 ; Oh et al, 2010 ; Rizzo et al, 2014 ).…”