Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats

Abstract

Although neurofibrillary tangle (NFT) formation is a central event in both familial and sporadic Alzheimer's disease (AD), neither cellular origin nor functional consequence of the NFTs are fully understood. This largely is due to the lack of available in vivo models for neurofibrillary degeneration (NFD). NFTs have only been identified in transgenic mice, bearing a transgene for a rare hereditary neurodegenerative disease, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP17). Epidemiological evidence suggests a much higher occurrence of dementia in stroke patients. This may represent the underlying cause of the pathogenesis of sporadic AD, which accounts for the majority of AD cases. We examined pathological markers of AD in a rodent stroke model. Here we show that after transient cerebral ischemia, hyperphosphorylated tau accumulates in neurons of the cerebral cortex in the ischemic area, forms filaments similar to those present in human neurodegenerative tauopathies and colocalizes with markers of apoptosis. As a potential underlying mechanism, we were able to determine that transient ischemia induced tau hyperphosphorylation and NFT-like conformations are associated with aberrant activation of cyclin dependent kinase 5 (Cdk5) and can be rescued by delivery of a potent, but non-specific cyclin dependent kinase inhibitor, roscovitine to the brain. Our study further indicates that accumulation of p35 and its calpain-mediated cleavage product, p25 may account for the deregulation of Cdk5 induced by transient ischemia. We conclude that Cdk5 may be the principal protein kinase responsible for tau hyperphosphorylation and may be a hallmark of the tauopathies in this stroke model.

Review paper Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?

“…Oxidative stress mediates β-amyloid peptide neurotoxicity, and the latter contributes to neuronal death following brain ischemia [52]. Along with β-amyloid peptide, tau protein changes in neuronal microtubules also contribute to the postischemic neurodegeneration in adult animals [68,70]. Abnormal phosphorylation and aggregation of tau protein lead to postischemic neuronal dysfunction [70].…”

“…Old age is associated with enhanced susceptibility to ischemic stroke and poor recovery from postischemic injury, but the cellular mechanisms which trigger these phenomena are only partially understood [30,46,[52][53][54]68,70]. Therefore, studying the complex processes underlying postischemic recovery of structural and cognitive functions in individuals a long time after birth is of considerable clinical importance [54].…”

Alzheimer's Factors in Ischemic Brain Injury

“…The above observations indicate that neuron ischemic apoptosis is connected with tau protein hyperphosphorylation (Wen et al, 2004b;Wen et al, 2007). Wen et al (2004cWen et al ( , 2007 noted that reversible brain ischemia is associated with neurofibrillary tangle-like tauopathy formation in the brain. These data provide groundwork for the cause of dementia after ischemic brain injury (Wen et al, 2004c).…”

“…The relationship between brain ischemic injury dementia and Alzheimer's disease type dementia is recently much debated. The mechanisms of the progressive cognitive decline after ischemic brain injury are not yet clear but animal investigations have demonstrated an increase in expression and processing of amyloid precursor protein to -amyloid peptide (Pluta et al, 1994b;Pluta et al, 1997b;Pluta et al, 1997c;Pluta et al, 1998b;Lin et al, 1999;Shi et al, 2000;Lin et al, 2001;Badan et al, 2004;Pluta et al, 2009) and an increase in the phosphorylation of tau protein (Dewar, Dawson 1995;Wen et al, 2004b;Wen et al, 2004c, Wen et al, 2007. Moreover, the common mechanism that links progressive cognitive decline after ischemic brain injury and during Alzheimer's disease is neuroinflammation (Koistinaho et al, 2002), which can cause gradual neurodegeneration during prolonged face of injury.…”

Análisis comparativo de marcadores de lesión en modelos de isquemia cerebral focal y global en ratas

“…La demencia se ha correlacionado con la presencia de taupatía en humanos (19,49), incluyendo la enfermedad de Alzheimer, la enfermedad de Parkinson y la demencia frontotemporal, lo cual sugiere que la proteína tau patológica es un marcador de progresión de la lesión cerebral (19,21).…”