19 research outputs found
Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo
The aberrant hyperactivation of Cyclin-dependent kinase 5 (Cdk5), by the production of its truncated activator p25, results in the formation of hyperphosphorylated tau, neuroinflammation, amyloid deposition, and neuronal death in vitro and in vivo. Mechanistically, this occurs as a result of a neurotoxic insult that invokes the intracellular elevation of calcium to activate calpain, which cleaves the Cdk5 activator p35 into p25. It has been shown previously that the p25 transgenic mouse as a model to investigate the mechanistic implications of p25 production in the brain, which recapitulates deregulated Cdk5-mediated neuropathological changes, such as hyperphosphorylated tau and neuronal death. To date, strategies to inhibit Cdk5 activity have not been successful in targeting selectively aberrant activity without affecting normal Cdk5 activity. Here we show that the selective inhibition of p25/Cdk5 hyperactivation in vivo, through overexpression of the Cdk5 inhibitory peptide (CIP), rescues against the neurodegenerative pathologies caused by p25/Cdk5 hyperactivation without affecting normal neurodevelopment afforded by normal p35/Cdk5 activity. Tau and amyloid pathologies as well as neuroinflammation are significantly reduced in the CIP-p25 tetra transgenic mice, whereas brain atrophy and subsequent cognitive decline are reversed in these mice. The findings reported here represent an important breakthrough in elucidating approaches to selectively inhibit the p25/Cdk5 hyperactivation as a potential therapeutic target to reduce neurodegeneration
A Fluorescent Glycolipid-Binding Peptide Probe Traces Cholesterol Dependent Microdomain-Derived Trafficking Pathways
10.1371/journal.pone.0002933PLoS ONE38
Pin1-dependent Prolyl Isomerization Modulates the Stress-induced Phosphorylation of High Molecular Weight Neurofilament Protein*
Aberrant phosphorylation of neuronal cytoskeletal proteins is a key
pathological event in neurodegenerative disorders such as Alzheimer disease
(AD) and amyotrophic lateral sclerosis, but the underlying mechanisms are
still unclear. Previous studies have shown that Pin1, a peptidylprolyl
cis/trans-isomerase, may be actively involved in the regulation of
Tau hyperphosphorylation in AD. Here, we show that Pin1 modulates oxidative
stress-induced NF-H phosphorylation. In an in vitro kinase assay, the
addition of Pin1 substantially increased phosphorylation of NF-H KSP repeats
by proline-directed kinases, Erk1/2, Cdk5/p35, and JNK3 in a
concentration-dependent manner. In vivo, dominant-negative (DN) Pin1
and Pin1 small interfering RNA inhibited epidermal growth factor-induced NF-H
phosphorylation. Because oxidative stress plays an important role in the
pathogenesis of neurodegenerative diseases, we studied the role of Pin1 in
stressed cortical neurons and HEK293 cells. Both hydrogen peroxide
(H2O2) and heat stresses induce phosphorylation of NF-H
in transfected HEK293 cells and primary cortical cultures. Knockdown of Pin1
by transfected Pin1 short interference RNA and DN-Pin1 rescues the effect of
stress-induced NF-H phosphorylation. The H2O2 and heat
shock induced perikaryal phospho-NF-H accumulations, and neuronal apoptosis
was rescued by inhibition of Pin1 in cortical neurons. JNK3, a brain-specific
JNK isoform, is activated under oxidative and heat stresses, and inhibition of
Pin1 by Pin1 short interference RNA and DN-Pin1 inhibits this pathway. These
results implicate Pin1 as a possible modulator of stress-induced NF-H
phosphorylation as seen in neurodegenerative disorders like AD and amyotrophic
lateral sclerosis. Thus, Pin1 may be a potential therapeutic target for these
diseases
Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease
10.3233/JAD-170093JOURNAL OF ALZHEIMERS DISEASE6041429-144
Cdk5-Mediated Phosphorylation of delta-Catenin Regulates Its Localization and GluR2-Mediated Synaptic Activity
10.1523/JNEUROSCI.6062-09.2010JOURNAL OF NEUROSCIENCE30258457-8467United State