Long- and short-term CDK5 knockdown prevents spatial memory dysfunction and tau pathology of triple transgenic Alzheimer’s mice

Abstract

CDK5 is a member of the cyclin-dependent kinase family with diverse functions in both the developing and mature nervous system. The inappropriate activation of CDK5 due to the proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles and chronic neurodegeneration. At 18 months of age 3xTg-AD mice were sacrificed after 1 year (long term) or 3 weeks (short term) of CDK5 knockdown. In long-term animals CDK5 knockdown prevented insoluble Tau formation in the hippocampi and prevented spatial memory impairment. In short-term animals, CDK5 knockdown showed reduction of CDK5, reversed Tau aggregation, and improved spatial memory compared to scrambled treated old 3xTg-AD mice. Neither long-term nor short-term CDK5 knock-down had an effect on old littermates. These findings further validate CDK5 as a target for Alzheimer’s disease both as a preventive measure and after the onset of symptoms.

CDK5 Knockdown Prevents Hippocampal Degeneration and Cognitive Dysfunction Produced by Cerebral Ischemia

“…Such vectors exhibit conserved silencing efficiency and effects on specific substrates, as we have verified in an Alzheimer's disease mouse model. 31 Several studies have described the administration of siRNA against pathogenic genes involved in cerebral ischemia-induced apoptotic cell death and inflammation. 32 However, it is important to emphasize that in such studies, the siRNA was delivered before the ischemic event, restricting the translation of such a protocol into clinical practice.…”

The Role of Cdk5 in Alzheimer’s Disease

“…Among these kinases, Cdk5 is particularly interesting because it may play a crucial role in the pathogenesis of AD and regulate activity of other critical kinases including Gsk-3β. An increasing number of studies in vitro and in vivo have shown that Cdk5 has a strong relationship with the phosphorylation of tau and the progression of neurofibrillary tangles [62,63]. Cdk5 mediated-hyperphosphorylation of tau makes tau no longer connect with the microtubules but aggregates into the filaments and tangles, ultimately leading to synaptic loss and neuronal death.…”

CDK5 knockdown in astrocytes provide neuroprotection as a trophic source via Rac1

“…Studies from our group have demonstrated that CDK5 silencing with RNA interference reduces pathological markers, such as NFTs, and improves cognitive function in triple-transgenic AD mice (Castro-Alvarez et al, 2014a;Piedrahita et al, 2010). However, the possible roles of the CDK5 protein and p35, the specific activator of CDK5 in astrocytes, are associated with regulation of the microtubule cytoskeleton and formation of the glial scar after scratch wounds (He et al, 2007).…”

“…Under pathological conditions, the microtubule-associated protein tau (a substrate of CDK5) is hyperphosphorylated by CDK5 and other kinases, which induces the formation of toxic intracellular aggregates in both neurons and astrocytes. These aggregates are known as neurofibrillary tangles (NFTs), and are considered a pathological marker in AD and other tauopathies (Castro-Alvarez et al, 2014a, 2014bGarcía-Matas et al, 2008).…”