In previous studies, we and others showed evidence for the aberrant re-expression of a series of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease (AD). That a mitotic cell cycle-related mechanism may play an important role in disease pathogenesis is highlighted by the earlier occurrence of cell cycle proteins compared to abnormal tau in AD and by their appearance at the very earliest prodrominal phase of disease (i.e., mild cognitive impairment). Furthermore, that cell cycle proteins are representative of a true cell cycle, rather than being an epiphenomena of other processes, is evident from evidence showing that there is a true mitotic alteration that leads to DNA replication (i.e., S phase) in neurons in AD. These findings led us to develop a novel hypothesis that neurodegeneration in AD, like cancer, is a disease of inappropriate cell cycle control. In support of this notion, we found that the expression a powerful cell cycle inducer, MYC, drives primary neurons to re-enter the cell cycle and, moreover, that MYC-induced cell cycle re-entry leads to tau phosphorylation. Based on these in vitro findings, we have recently developed a bitransgenic mouse model that inducibly expresses MYC specifically in forebrain neurons (CaMKII-MYC). In our preliminary analysis of these CaMKII-MYC animals, we found that MYC expression in this animal model: 1) drives neurons to enter the cell cycle;2) causes hyperphosphorylation of tau;3) leads to accumulation of intraneuronal AB;4) results in a """"""""neurodegenerative"""""""" (TUNEL) Phenotype;5) leads to gliosis;and 6) causes major cognitive deficits (Y- maze and MWM). Since the aforementioned pathological and behavioral changes are all synonymous with AD, this mouse may be a very useful model of disease pathogenesis. The goal of this proposal is to further delineate the importance of neuronal cell cycle re-entry using this CaMKII-MYC animal model (Aim 1) and examine the effects of neuronal cell cycle re-entry under A2-rich conditions by analysis of a triple transgenic Tg2576/CaMKII-MYC mice (Aim 2). At the conclusion of these studies, we hope to not only have advanced our understanding of fundamental mechanisms that control neuronal cell cycle, particularly as it applies to AD, but also suggest novel therapies that could be manipulated to either prevent initiation of degeneration or stimulate recovery of damaged neurons in neurodegenerative conditions. Alzheimer disease is the leading cause of dementia in the United States. Recent studies have implicated inappropriate cell cycle re-entry in vulnerable neurons as playing a role in the neuronal loss, pathology, and cognitive impairment that are characteristic of the disease. This proposal will help to clarify the role of cell cycle re-entry in Alzheimer disease by characterizing a novel transgenic mouse model of cell cycle re-entry and delineating the effects of cell cycle re-entry in an amyloid-rich environment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028679-03
Application #
7796589
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Refolo, Lorenzo
Project Start
2008-03-01
Project End
2013-02-28
Budget Start
2010-03-15
Budget End
2011-02-28
Support Year
3
Fiscal Year
2010
Total Cost
$318,632
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Feng, Lianyuan; Sharma, Aruna; Niu, Feng et al. (2018) TiO2-Nanowired Delivery of DL-3-n-butylphthalide (DL-NBP) Attenuates Blood-Brain Barrier Disruption, Brain Edema Formation, and Neuronal Damages Following Concussive Head Injury. Mol Neurobiol 55:350-358
Ozkizilcik, Asya; Sharma, Aruna; Muresanu, Dafin F et al. (2018) Timed Release of Cerebrolysin Using Drug-Loaded Titanate Nanospheres Reduces Brain Pathology and Improves Behavioral Functions in Parkinson's Disease. Mol Neurobiol 55:359-369
Lafuente, José Vicente; Sharma, Aruna; Muresanu, Dafin F et al. (2018) Repeated Forced Swim Exacerbates Methamphetamine-Induced Neurotoxicity: Neuroprotective Effects of Nanowired Delivery of 5-HT3-Receptor Antagonist Ondansetron. Mol Neurobiol 55:322-334
Ozkizilcik, Asya; Williams, Roger; Tian, Z Ryan et al. (2018) Synthesis of Biocompatible Titanate Nanofibers for Effective Delivery of Neuroprotective Agents. Methods Mol Biol 1727:433-442
Patnaik, Ranjana; Sharma, Aruna; Skaper, Stephen D et al. (2018) Histamine H3 Inverse Agonist BF 2649 or Antagonist with Partial H4 Agonist Activity Clobenpropit Reduces Amyloid Beta Peptide-Induced Brain Pathology in Alzheimer's Disease. Mol Neurobiol 55:312-321
Sharma, Aruna; Muresanu, Dafin F; Lafuente, José Vicente et al. (2018) Cold Environment Exacerbates Brain Pathology and Oxidative Stress Following Traumatic Brain Injuries: Potential Therapeutic Effects of Nanowired Antioxidant Compound H-290/51. Mol Neurobiol 55:276-285
Sharma, Hari Shanker; Muresanu, Dafin Fior; Lafuente, José Vicente et al. (2018) Co-Administration of TiO2 Nanowired Mesenchymal Stem Cells with Cerebrolysin Potentiates Neprilysin Level and Reduces Brain Pathology in Alzheimer's Disease. Mol Neurobiol 55:300-311
Sharma, Aruna; Menon, Preeti K; Patnaik, Ranjana et al. (2017) Novel Treatment Strategies Using TiO2-Nanowired Delivery of Histaminergic Drugs and Antibodies to Tau With Cerebrolysin for Superior Neuroprotection in the Pathophysiology of Alzheimer's Disease. Int Rev Neurobiol 137:123-165
Sharma, Aruna; Menon, Preeti; Muresanu, Dafin F et al. (2016) Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair. CNS Neurol Disord Drug Targets 15:1092-1117
Hradek, Alex C; Lee, Hyun-Pil; Siedlak, Sandra L et al. (2015) Distinct chronology of neuronal cell cycle re-entry and tau pathology in the 3xTg-AD mouse model and Alzheimer's disease patients. J Alzheimers Dis 43:57-65

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