Activity-dependent p25 generation regulates synaptic plasticity and Aβ-induced cognitive impairment

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Cyclin-dependent kinase 5 (CDK5) and its activator p35 are crucial for neuronal functions.
• Pathological cleavage of p35 generates p25, linked to neurodegenerative diseases.
• The physiological role of p25 production remained unclear.

Purpose of the Study:

• To investigate the physiological generation of p25 during neuronal activity.
• To elucidate the role of p25 in synaptic plasticity, memory, and Alzheimer's disease (AD) pathology.
• To develop a genetic tool to prevent p25 formation.

Main Methods:

• Generation of a knockin mouse model (Δp35KI) with a calpain-resistant p35 mutant.
• Assessment of synaptic plasticity (long-term depression) and memory extinction in Δp35KI mice.
• Crossbreeding Δp35KI mice with 5XFAD AD model mice to evaluate Aβ-induced pathology.

Main Results:

• p25 is physiologically generated in a GluN2B- and CaMKIIα-dependent manner during neuronal activity.
• Δp35KI mice showed impaired long-term depression and memory extinction, linked to persistent GluA1 phosphorylation.
• Crossing Δp35KI mice with 5XFAD mice ameliorated Aβ-induced synaptic depression and cognitive deficits.

Conclusions:

• p25 production has a physiological role in synaptic plasticity and memory formation.
• Targeting p25 generation may offer therapeutic benefits for AD and other neurodegenerative conditions.
• This study provides novel insights into p25 function in both normal synaptic processes and AD pathogenesis.