Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia

Abstract

Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δ mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:Δp35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation. Accumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes, such as neuroinflammation, synaptic loss, Aβ accumulation, and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the Δ transgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we used this mouse model to elucidate the role of p25/Cdk5 in FTD mutant tau-mediated pathology. We also used a frontotemporal dementia patient-derived induced pluripotent stem cell carrying the Tau P301L mutation and generated isogenic lines in which p35 is replaced with noncleavable mutant Δp35. Our data suggest that p25/Cdk5 plays an important role in tauopathy in both mouse and human model systems.

CB1R regulates CDK5 signaling and epigenetically controls Rac1 expression contributing to neurobehavioral abnormalities in mice postnatally exposed to ethanol

“…2c). The CDK5/p25 kinase activity hyperphosphorylates tau (major microtubule-associated protein), alters the cytoskeleton, and promotes neuronal death [38]. Therefore, we further evaluated PHF1 (phosphorylated tau) levels in the HP and NC brain regions.…”

Using brain organoids to study human neurodevelopment, evolution and disease

“…There is a big effort being made to model neurodevelopmental disorders such as microcephaly (Gabriel et al, 2016;Lancaster et al, 2013), macrocephaly (Li, Muffat, et al, 2017), lissencephaly (Bershteyn et al, 2017;Iefremova et al, 2017;Li, Muffat, et al, 2017), periventricular heterotopia (Klaus et al, 2019;O'Neill, Kyrousi, Einsiedler, et al, 2018;O'Neill, Kyrousi, Klaus, et al, 2018) and autism spectrum disorder (Mariani et al, 2015). Other types of diseases, which were already modeled using brain organoids are genetic, mental and neurodegenerative disorders such as schizophrenia (Ye et al, 2017), Sandhoff disease (Allende et al, 2018), Alzheimer (Raja et al, 2016), frontotemporal dementia (Seo et al, 2017) and Rett-syndrome (Mellios et al, 2018). Finally organoids are an ideal model for drug development or viral transduction and in particular organoids have been used to investigate the function of Zika virus on human brain development (Dang et al, 2016;Garcez et al, 2016;Qian et al, 2017).…”

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“…In Alzheimer's disease, tau is translocated to the somatodendritic compartment, where it undergoes hyperphosphorylation, misfolding and aggregation, thus giving rise to neurofibrillary tangles and neuropil threads. The presence of senile plaques (SP) and neurofibrillary tangles (NFT) play a critical role in the pathogenesis of Alzheimer"s dementia 32,33 .…”