TNF-α Mediates PKR-Dependent Memory Impairment and Brain IRS-1 Inhibition Induced by Alzheimer’s β-Amyloid Oligomers in Mice and Monkeys

Abstract

Alzheimer's disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that β-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR(-/-) and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss.

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…These observations led to the intuitive interpretation that XBP1 levels might be reduced in AD models and/or human patients. Surprisingly, endogenous XBP1 was undetectable in AD models that produced high levels of oligomeric Aβ or in human brains postmortem (19), whereas neurons exposed to Aβ oligomers showed a significant increase of XBP1 levels (42,167). These discrepancies likely reflect a compensatory mechanism triggered by acute exposure to Aβ oligomers, whereas chronic exposure to these neurotoxins, which is more reflective of the in vivo situation, causes an overdrive and collapse of the system.…”

“…Importantly, some pharmaceutical companies, namely Atherys, SanBio and Brain Storm Therapeutics, finalized several MSC therapy-based phase II clinical trials involving ischemic stroke and amyotrophic lateral sclerosis patients and reported no adverse effects whatsoever (200). Furthermore, modulating the IRE1α-XBP1 pathway with small-molecule compounds could be a promising approach for disease therapy (201), since various studies have reported that XBP1 protects against oligomeric forms of prion protein or α-synuclein (167,(202)(203)(204). Nonetheless, the majority of these molecules are inhibitors that selectively Indeed, conventional wisdom holds that an increase in Aβ load damages neuronal networks composed of memory engram cells.…”

Premature or pathological aging: longevity

“…In vitro and animal experiments by Fernanda De Felice and Sérgio Ferreira have shown that insulin protects neurons from the action of oligomers (LOURENÇO et al, 2013). In this work the authors presented new neuronal mechanisms that cause loss of synapses in mice and monkeys similar to Alzheimer's.…”

“…However, in the short term it may be more realistic to think of ways to slow down the progress of brain injuries leading to Alzheimer's and prevent as much as possible the appearance of cognitive problems that gradually reduce the quality of life of patients. Details of the latest research on Alzheimer's mentioned above can be found in recent publications (MARTINS et al, 2005;MORI et al, 2008;ANDRADE-MORAES et al, 2013;LOURENÇO et al, 2013;BALTHAZAR et al, 2014).…”

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

“…Importantly, targeting deletion of PERK expression in the context of AD restored synaptic function due to the recovery of protein synthesis of synaptic proteins, improving memory capacity and synaptic transmission [52,53]. Similarly, ablating the expression of other eIF2α kinases like PKR and GCN-2 impact synaptic function in AD models [54,52]. ATF4 expression was also recently shown to control axonal degeneration in AD models through a cell-nonautonomous mechanism [55].…”