PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions

Abstract

Brain lesions in Alzheimer's disease (AD) include amyloid plaques made of Aβ peptides and neurofibrillary tangles composed of hyperphosphorylated tau protein with synaptic and neuronal loss and neuroinflammation. Aβ oligomers can trigger tau phosphorylation and neuronal alterations through activation of neuronal kinases leading to progressive cognitive decline. PKR is a ubiquitous pro‐apoptotic serine/threonine kinase, and levels of activated PKR are increased in AD brains and AD CSF. In addition, PKR regulates negatively memory formation in mice. To assess the role of PKR in an AD in vivo model, we crossed 5xFAD transgenic mice with PKR knockout (PKRKO) mice and we explored the contribution of PKR on cognition and brain lesions in the 5xFAD mouse model of AD as well as in neuron–microglia co‐cultures exposed to the innate immunity activator lipopolysaccharide (LPS). Nine‐month‐old double‐mutant mice revealed significantly improved memory consolidation with the new object location test, starmaze test, and elevated plus maze test as compared to 5xFAD mice. Brain amyloid accumulation and BACE1 levels were statistically decreased in double‐mutant mice. Apoptosis, neurodegeneration markers, and synaptic alterations were significantly reduced in double‐mutant mice as well as neuroinflammation markers such as microglial load and brain cytokine levels. Using cocultures, we found that PKR in neurons was essential for LPS microglia‐induced neuronal death. Our results demonstrate the clear involvement of PKR in abnormal spatial memory and brain lesions in the 5xFAD model and underline its interest as a target for neuroprotection in AD.

Translation from the Ribosome to the Clinic: Implication in Neurological Disorders and New Perspectives from Recent Advances

“…In addition to PERK, other kinases including double-stranded RNA-activated protein kinase (PKR), general control non-derepressible-2 kinase (GCN2), and heme-regulated inhibitor kinase (HRI), can phosphorylate eIF2α and together make up the integrated stress response (ISR). Enhanced PKR activation has been observed in patients and mouse models of AD, PD, and HD [38,39,40,41,42,43,44,45], and the inhibition of PERK, PKR, and GCN2 via genetic and pharmacologic means have shown beneficial effects [46,47,48,49]. Thus, despite eIF2α and the ISR being a protective mechanism that temporarily halts protein translation in order to alleviate further stress caused by protein misfolding and aggregation, chronic eIF2α-mediated shutdown of global protein synthesis may have substantial negative impact on various neuronal functions that require de novo protein production.…”

Neuroprotective effect of tormentic acid against memory impairment and neuro‑inflammation in an Alzheimer's disease mouse model

“…10A and B). However, these effects were attenuated by pre-treatment with 10 nM TA before exposure to aβ [25][26][27][28][29][30][31][32][33][34][35] . Together, these results indicated that Ta suppression of il-1β and TnFα expression is most likely associated with inhibition of nF-κB activation.…”

“…in the present study, Ta decreasedcaspase-3 activity and dna fragmentation levels in the PFc and HC of AD mice. Several previous studies demonstrated that in neuron-microglia co-cultures, aβ-induced neuron degeneration was dependent on the presence of microglia cells (34,35). Thus, inhibition of pro-inflammatory cytokines could offer an effective therapeutic strategy for the prevention of ad progression.…”

Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity and memory in mouse models of Alzheimer’s disease

“…Activation of the ISR and attenuation of brain protein synthesis have been implicated in memory deficits in AD ( 15, 16, 24–26 ) and in other neurodegenerative disease ( 13–23 ), supporting the notion that correcting defective brain protein synthesis might comprise an effective therapeutic target in AD. Because three out of four known eIF2α kinases have been shown to play pathogenic roles in AD ( 15, 16, 24, 25, 36, 37 ), identifying approaches that act downstream of eIF2α-P may comprise a more viable strategy to alleviate cognitive impairment than simultaneously targeting individual kinases. Here, we show that treatment with ISRIB, a small molecule compound that targets ISR downstream of eIF2α, restores synaptic plasticity and long-term memory defects in AD mouse models.…”