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Review
. 2012 Nov;43(8):655-62.
doi: 10.1016/j.arcmed.2012.10.015. Epub 2012 Nov 7.

Deregulated Cdk5 activity is involved in inducing Alzheimer's disease

Varsha Shukla  1 , Susan Skuntz, Harish C Pant
Affiliations
Review

Deregulated Cdk5 activity is involved in inducing Alzheimer's disease

Varsha Shukla et al. Arch Med Res. 2012 Nov.

Abstract

Alzheimer's disease (AD), the most devastating chronic neurodegenerative disease in adults, causes dementia and eventually, death of the affected individuals. Clinically, AD is characterized as late-onset, age-dependent cognitive decline due to loss of neurons in cortex and hippocampus. The pathologic corollary of these symptoms is the formation of senile plaques and neurofibrillary tangles. Senile plaques are formed due to accumulation of oligomeric amyloid beta (Aβ) forming plaques. This occurs due to the amyloidogenic processing of the amyloid precursor protein (APP) by various secretases. On the other hand, neurofibrillary tangles are formed due to hyperphosphorylation of cytoskeleton proteins like tau and neurofilament. Both are hyperphosphorylated by cyclin-dependent kinase-5 (Cdk5) and are part of the paired helical filament (PHF), an integral part of neurofibrillary tangles. Unlike other cyclin-dependent kinases, Cdk5 plays a very important role in the neuronal development. Cdk5 gets activated by its neuronal activators p35 and p39. Upon stress, p35 and p39 are cleaved by calpain resulting in truncated products as p25 and p29. Association of Cdk5/p25 is longer and uncontrolled causing aberrant hyperphosphorylation of various substrates of Cdk5 like APP, tau and neurofilament, leading to neurodegenerative pathology like AD. Additionally recent evidence has shown increased levels of p25, Aβ, hyperactivity of Cdk5, phosphorylated tau and neurofilament in human AD brains. This review briefly describes the above-mentioned aspects of involvement of Cdk5 in the pathology of AD and at the end summarizes the advances in Cdk5 as a therapeutic target.

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Figures

Figure 1
Figure 1
(A) Schematic representation of APP processing by various secretases under physiological and pathological conditions. (B–C) Cortex of a 9-month-old AD model mouse (5XFAD) with APP and PS1 mutations stained with antibody against Aβ42 (in red) and nuclear stain DAPI (in blue). Arrows indicate the presence of amyloid plaques. Bar = 20 μm.
Figure 2
Figure 2
Six isoforms of human tau. Absence of exon 2 and 3 (E2, E3) near the N-terminus of tau gives rise to 0N tau isoforms whereas presence of E2 gives rise to 1N and both E2 and E3 give rise to 2N tau isoforms. Similarly, presence or absence of R1-R4 repeats in the microtubule binding domain gives rise to 3R or 4R tau isoforms. The proline-rich domain is found in between the N and C terminal and is present in all six isoforms. Most of the phosphorylation sites are found in proline-rich domain.
Figure 3
Figure 3
Role of Cdk5/p35 in physiology. Under physiological conditions, Cdk5 is tightly regulated due to its neuron-specific promoter p35 and is involved in various biologically important processes as shown.
Figure 4
Figure 4
Cdk5-mediated phosphorylation sites detected on tau from Alzheimer brain. The sites are shown in red color and are mostly located in proline-rich domain with a few at the C-terminal.
See this image and copyright information in PMC

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