Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment

Abstract

SUMMARY Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of β-amyloid (Aβ)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Aβ-associated neurotoxicity and AD-like pathology.

TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice

“…P5, a 24aa peptide from p35, which, when modified as TFP5 (an N-terminal FITC fluorescent marker and a C-terminal TAT sequence to penetrate the blood-brain barrier) has been shown to specifically inhibit cdk5/p25 in a 5XFAD model mouse and alleviate AD-like phenotypes (including behavior) without affecting normal activity of cdk5/p35 [23]. Although a modest level of cdk5/p25 is produced in these mouse brains, it is insufficient as proof of the pathological role of p25, possibly because low, transient p25 levels are involved in normal synaptic activity [63]. Optimally, we require a model in which robust, sustained levels of p25 can be induced and regulated experimentally to test the efficacy of the TFP5 peptide.…”

S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

“…This could explain detection of SNO-GRIN2B, a subunit of the NMDAR, in the CK-p25 mice. Amyloid activation of the NMDAR can increase p25 production, possibly providing a feed-forward mechanism for SNO production (18). NMDARmediated p25 production and Cdk5 activation is thought to increase glycogen synthase kinase-3β (GSK3β) and TAU (Mapt) phosphorylation, two key mediators of neuronal death in AD, both of which we identified in the CK-p25 mice.…”

“…SNOTRAP (SNO trapping by triaryl phosphine) is a direct tagging technique that allows enrichment and identification of SNO-proteins and their cognate SNO-sites. Hyperactivation of cyclin-dependent kinase-5 (Cdk5) by its activator peptide, p25, leads to AD-like neurodegenerative pathology, and inhibition of p25 activity ameliorates AD phenotypes (18)(19)(20). The CK-p25 mouse model of AD-like neurodegeneration allows temporal characterization of neurodegeneration through inducible expression of the p25 activator peptide, leading to elevated amyloid-β levels and DNA damage, followed by synaptic loss, neuronal death, and cognitive impairments (21)(22)(23)(24).…”

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

“…One of the culprits of AD is the overactivation of calpains because of calcium homeostasis changes (see [160] for a critical review). Enhanced calpain activation produces augmented APP processing via BACE activation and augmented Aβ deposit [161], increases tau-mediated neuropathology [162], and disrupts the functionality of kinases such as CDK5 by pushing the cleavage of the CDK5 activator p35 [163], but also induces microgliosis, somatodendritic dystrophy, and increased mortality while the endogenous calpain inhibitor calpastatin is knocked down in animal models of AD [164]. This evidence supports the possible use of calpain inhibitors as a therapeutic treatment in AD [153][154][155].…”