title: TFP5, a peptide derived from p35, a Cdk5 neuronal activator, rescues cortical neurons from glucose toxicity.
abstract: Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer's disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. Cyclin dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39, found principally in neurons and in pancreatic β cells. Recent studies suggest that Cdk5 hyperactivity is a possible link between neuropathology seen in AD and diabetes. Previously, we identified P5, a truncated 24-aa peptide derived from the Cdk5 activator p35, later modified as TFP5, so as to penetrate the blood-brain barrier after intraperitoneal injections in AD model mice. This treatment inhibited abnormal Cdk5 hyperactivity and significantly rescued AD pathology in these mice. The present study explores the potential of TFP5 peptide to rescue high glucose (HG)-mediated toxicity in rat embryonic cortical neurons. HG exposure leads to Cdk5-p25 hyperactivity and oxidative stress marked by increased reactive oxygen species production, and decreased glutathione levels and superoxide dismutase activity. It also induces hyperphosphorylation of tau, neuroinflammation as evident from the increased expression of inflammatory cytokines like TNF-α, IL-1β, and IL-6, and apoptosis. Pretreatment of cortical neurons with TFP5 before HG exposure inhibited Cdk5-p25 hyperactivity and significantly attenuated oxidative stress by decreasing reactive oxygen species levels, while increasing superoxide dismutase activity and glutathione. Tau hyperphosphorylation, inflammation, and apoptosis induced by HG were also considerably reduced by pretreatment with TFP5. These results suggest that TFP5 peptide may be a novel candidate for type 2 diabetes therapy.
authors: Laboratory of Neuronal Cytoskeletal protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors: B K
authors: BK
authors: Binukumar
authors: Laboratory of Neuronal Cytoskeletal protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA Department of Nephrology, Ningxia People's Hospital, Yinchuan, Ningxia Province, China.
authors: Ya-Li
authors: YL
authors: Zheng
authors: Laboratory of Neuronal Cytoskeletal protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors: Varsha
authors: V
authors: Shukla
authors: Laboratory of Neuronal Cytoskeletal protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors: Niranjana D
authors: ND
authors: Amin
authors: Laboratory of Neuronal Cytoskeletal protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors: Philip
authors: P
authors: Grant
authors: Laboratory of Neuronal Cytoskeletal protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors: Harish C
authors: HC
authors: Pant
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D004195:Disease Models, Animal; D005947:Glucose / Q000633:toxicity*; D008969:Molecular Sequence Data; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D010446:Peptide Fragments / Q000502:physiology*; D010770:Phosphotransferases / Q000737:chemistry / Q000502:physiology*; D051381:Rats
chemical_list: C492235:Cdk5r1 protein, rat; D010446:Peptide Fragments; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D005947:Glucose
keywords: Alzheimer's disease; cyclin dependent kinase 5; diabetes; neuroinflammation; oxidative stress