Department of Neurosciences
Alzheimer's disease (AD) is the most common cause of dementia worldwide. The cause of the disease is not completely understood and currently there is no cure for AD. Genetic and cell biological studies show that amyloid precursor protein (APP) is intimately associated with AD pathogenesis.We generated a transgenic mice expressing a small fragment of APP called AICD and demonstrated that AICD-Tg mice develop major AD-like pathologies such as tau tangles, neurodegeneration, neuroinflammation and loss of memory.
In the past year we have focused on understanding the basis of memory loss in AICD-Tg mice. Towards this goal, we examined the brains electrophysiologically and showed that they were deficient in long-term potentiation (LTP). We also performed ultrastructural studies using 3-D electron microscopy and found that AICD-Tg mice exhibit smaller and fewer synapses compared wild-type controls. These findings provide structural and functional basis for memory loss in AICD-Tg mice.
We are currently exploring the contribution of neuroinflammation to AD-pathologies and memory loss. It is known that chronic neuroinflammation and inflammatory cytokines inhibit synaptic communication and lead to axonal loss and neuronal death. We previously showed that anti-inflammatory treatments prevent AD-pathologies in AICD-Tg mice. We are currently collaborating with a biotech company to study the efficacy of stem cells against AD. We are also examining the efficacy of drugs targeted towards Tau in rescuing AD-associated memory loss. Our future goals are aimed at developing and validating alternative therapeutic strategies against AD since amyloid-lowering therapies have not been successful.
Morris JK, Chomyk A, Song P, Parker N, Deckard S, Trapp BD, Pimplikar SW, Dutta R. (2015) Decrease in levels of the evolutionarily conserved microRNA miR-124 affects oligodendrocyte numbers in Zebrafish, Danio rerio. Invert Neurosci 15(3):4.
Margevicius DR, Bastian C, Fan Q, Davis RJ, Pimplikar SW. (2015) JNK-interacting protein 1 mediates Alzheimer's-like pathological features in AICD-transgenic mice. Neurobiol Aging 36(8):2370-9.
Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, Xu G, Margevicius D, Karlo JC, Sousa GL, Cotleur AC, Butovsky O, Bekris L, Staugaitis SM, Leverenz JB, Pimplikar SW, Landreth GE, Howell GR, Ransohoff RM, Lamb BT. (2015) TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med 212(3):287-95. PMID:25732305; PMCID:PMC4354365
Pimplikar SW. (2014) Neuroinflammation in Alzheimer's disease: from pathogenesis to a therapeutic target. J Clin Immunol 34 Suppl 1:S64-9. PMID:24711006
Ghosal K, Stathopoulos A, Thomas D, Phenis D, Vitek MP, Pimplikar SW. (2013) The apolipoprotein-E-mimetic COG112 protects amyloid precursor protein intracellular domain-overexpressing animals from Alzheimer's disease-like pathological features. Neurodegener Dis 12(1):51-8. PMID:22965147
Pimplikar SW. (2012) Clinical and biomarker changes in Alzheimer's disease. N Engl J Med 367(21):2050-1; author reply 2051-2. PMID:23171105
Song P, Pimplikar SW. (2012) Knockdown of amyloid precursor protein in zebrafish causes defects in motor axon outgrowth. PLoS One 7(4):e34209. PMID:22545081; PMCID:PMC3335837
Pimplikar SW, Ghosal K. (2011) Amyloid precursor protein: more than just neurodegeneration. Stem Cell Res Ther 2(5):39. PMID:22000643; PMCID:PMC3308036
Pimplikar SW, Suryanarayana A. (2011) Detection of APP intracellular domain in brain tissue. Methods Mol Biol 670:85-91. PMID:20967585
Ghosal K, Pimplikar SW. (2011) Aging and excitotoxic stress exacerbate neural circuit reorganization in amyloid precursor protein intracellular domain transgenic mice. Neurobiol Aging 32(12):2320.e1-9. PMID:20493588; PMCID:PMC2928862
Vogt DL, Thomas D, Galvan V, Bredesen DE, Lamb BT, Pimplikar SW. (2011) Abnormal neuronal networks and seizure susceptibility in mice overexpressing the APP intracellular domain. Neurobiol Aging 32(9):1725-9. PMID:19828212; PMCID:PMC2889215