Principal Investigator Li-Huei Tsai
Alzheimer’s disease (AD) is a devastating and irreversible brain disorder that eventually leads to dementia and death. Cyclin-dependent kinase 5 (Cdk5) is a brain-specific protein serine/threonine kinase essential for brain development, synaptic plasticity, learning, and memory. We have shown that the hyperactivation of Cdk5 occurs when its regulatory protein p35 is cleaved by the Ca2+-activated protease calpain, under neurotoxic conditions, to liberate the carboxyl-terminal fragment p25. We hypothesized that p25 generation and accumulation play important roles in AD-like neurodegeneration. We created an inducible mouse model of p25 accumulation (the CK-p25 mouse) that displays key pathological hallmarks of AD, including profound neuronal loss in the forebrain, increased β-amyloid (Ab) peptide production, tau pathology, and severe cognitive impairment. In this model, increased β-amyloid peptide levels are observed prior to neuronal loss; furthermore, reducing β-amyloid peptide production ameliorates memory deficits in the CK-p25 mouse model, indicating that this event operates synergistically with p25, leading to the manifestation of neurodegeneration and memory impairment.
To further decipher the role of p25 generation in neurodegeneration, we created a mouse “knock-in” model whereby endogenous p35 gene is replaced by a mutant p35 resistant to calpain cleavage (Δp35KI). Δp35KI mice show normal hippocampus dependent learning and memory and LTP. However, they exhibit impaired hippocampal long-term depression (LTD). Moreover, Δp35KI hippocampal neurons are resistant to Ab peptide induced synaptic depression. The 5XFAD model is a well-established AD mouse model exhibiting abundant amyloid plaque pathology, inflammation and memory deficits by 6-month old. Interestingly, memory deficits are not observed in the Δp35KI/5XFAD compound mice, and the animals also show ameliorated inflammatory response and reduced Ab levels. These results strongly suggest that p25 mediates Ab peptide-associated pathology.
Currently, we are evaluating whether p25 generation also plays a role in Tau-mediated pathology. In addition, we are using Crispr/Cas-mediated genome editing to create calpain-resistant p35 alleles in human pluripotent stem cells (iPSCs) derived from AD patients (see below) to evaluate the role of p25 generation in the degeneration of human neurons and to create human cellular models of AD for therapeutic investigation.