Studies have shown that CDK5 and GSK3 are able to phosphorylate tau. Since hyperphosphorylated tau accumulates in the NFTs, the role of these kinases in tau hyperphosphorylation is under intense investigation. CDK5 by itself is inactive and requires association with p35 (or p39) to get activated. Indeed, p35 knockout mice show a similar phenotype as CDK5 -/- mice, although the mice are viable and fertile.
P35 is cleaved (e.g., by calpain, the Ca++ activated cysteine protease, after induction of ischemia in the brain) to generate a shorter fragment of p25 which constitutively activates CDK5. Accumulation of p25 in the brains of AD patients has also been reported. An earlier study by Ahlijanian et al. showed that p25 overexpressing mice, in the presence of endogenous p35, produced hyperphosphorylated tau and neurofilaments accompanied with disturbances in neuronal cytoskeleton. In the present study, Patzke et al. generated p25 transgenic mice in p35 null background and report that p25 can partially rescue p35-/- phenotype (cytoarchitecture in the brain, restoration of hippocampal morphology, and positioning of neurons in specific layers). These changes were accompanied by partial restoration of phosphorylation of mDab1, but not of PSD-95 and tau. These observations are mostly consistent with the earlier studies of Ahlijanian et al. However, Patzke et al., unlike the earlier study, found no hyperphosphorylation of tau or neurofilaments in their p25 transgenic mice that expressed endogenous p35. The authors suggest that these differences could be accounted for by the lower expression levels of p25 in their transgenic mice. It should be noted that Takashima et al. (see also Bian et al., 2002) also found no hyperphosphorylation of tau in their p25 transgenic animals. These differences also reveal the difficulties in comparing data from mice with different genetic backgrounds.
In summary, these studies clearly show that p25 can partially replace p35 function and rescue neuronal abnormalities found in p35-/- mice. These studies, however, do not show to what extent, if any, p25 can be responsible for tau hyperphosphorylation observed in AD.
References:
Ahlijanian MK, Barrezueta NX, Williams RD, Jakowski A, Kowsz KP, McCarthy S, Coskran T, Carlo A, Seymour PA, Burkhardt JE, Nelson RB, McNeish JD.
Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5.
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2910-5.
PubMed.
Takashima A, Murayama M, Yasutake K, Takahashi H, Yokoyama M, Ishiguro K.
Involvement of cyclin dependent kinase5 activator p25 on tau phosphorylation in mouse brain.
Neurosci Lett. 2001 Jun 22;306(1-2):37-40.
PubMed.
Bian F, Nath R, Sobocinski G, Booher RN, Lipinski WJ, Callahan MJ, Pack A, Wang KK, Walker LC.
Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice.
J Comp Neurol. 2002 May 6;446(3):257-66.
PubMed.
Comments
Case Western Reserve University
Studies have shown that CDK5 and GSK3 are able to phosphorylate tau. Since hyperphosphorylated tau accumulates in the NFTs, the role of these kinases in tau hyperphosphorylation is under intense investigation. CDK5 by itself is inactive and requires association with p35 (or p39) to get activated. Indeed, p35 knockout mice show a similar phenotype as CDK5 -/- mice, although the mice are viable and fertile.
P35 is cleaved (e.g., by calpain, the Ca++ activated cysteine protease, after induction of ischemia in the brain) to generate a shorter fragment of p25 which constitutively activates CDK5. Accumulation of p25 in the brains of AD patients has also been reported. An earlier study by Ahlijanian et al. showed that p25 overexpressing mice, in the presence of endogenous p35, produced hyperphosphorylated tau and neurofilaments accompanied with disturbances in neuronal cytoskeleton. In the present study, Patzke et al. generated p25 transgenic mice in p35 null background and report that p25 can partially rescue p35-/- phenotype (cytoarchitecture in the brain, restoration of hippocampal morphology, and positioning of neurons in specific layers). These changes were accompanied by partial restoration of phosphorylation of mDab1, but not of PSD-95 and tau. These observations are mostly consistent with the earlier studies of Ahlijanian et al. However, Patzke et al., unlike the earlier study, found no hyperphosphorylation of tau or neurofilaments in their p25 transgenic mice that expressed endogenous p35. The authors suggest that these differences could be accounted for by the lower expression levels of p25 in their transgenic mice. It should be noted that Takashima et al. (see also Bian et al., 2002) also found no hyperphosphorylation of tau in their p25 transgenic animals. These differences also reveal the difficulties in comparing data from mice with different genetic backgrounds.
In summary, these studies clearly show that p25 can partially replace p35 function and rescue neuronal abnormalities found in p35-/- mice. These studies, however, do not show to what extent, if any, p25 can be responsible for tau hyperphosphorylation observed in AD.
References:
Ahlijanian MK, Barrezueta NX, Williams RD, Jakowski A, Kowsz KP, McCarthy S, Coskran T, Carlo A, Seymour PA, Burkhardt JE, Nelson RB, McNeish JD. Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2910-5. PubMed.
Takashima A, Murayama M, Yasutake K, Takahashi H, Yokoyama M, Ishiguro K. Involvement of cyclin dependent kinase5 activator p25 on tau phosphorylation in mouse brain. Neurosci Lett. 2001 Jun 22;306(1-2):37-40. PubMed.
Bian F, Nath R, Sobocinski G, Booher RN, Lipinski WJ, Callahan MJ, Pack A, Wang KK, Walker LC. Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice. J Comp Neurol. 2002 May 6;446(3):257-66. PubMed.
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