Assessing memory in mouse models of Alzhiemer's disease

Borchelt, David R.

Abstract

We have generated two independent lines of transgenic (Tg) mice (lines C3- 3 and E1-2) that express mutant humanized amyloid precursor protein (APP) (Mo/Hu-APPswe) at levels sufficient to induce beta-amyloid (Abeta) deposition between 20 and 24 months of age. These animals have been mated C57BL/6J mice for ten generations to obtain congenic animals (99.99%). In Project 1, we propose to conduct behavior tests (Morris water maze, eight-arm radial maze, and Y-maze) designed to examine the cognitive abilities of our congenic/Tg Mo/Hu-APPswe mice. Following behavioral testing, each cohort (6-, and 14-, 22- and 28 months of age) will be humanely sacrificed to provide tissues for detailed neuropathological/neurochemical evaluations (Project 2). Together, these studies will determine whether changes in cognitive performance correlate with specific neuropathological/neurochemical evaluations (Project 2). Together, these studies will determine whether changes in cognitive performance correlate with specific neuropathological/neurochemical abnormalities. Importantly, our planned study will, for the fist time, behaviorally characterize mutant APP Tg mice that are congenic on a single inbred strain background and will be the first to confirm findings of two independent lines of mice that express similar levels of mutant APP and develop Abeta deposits at similar ages. To explore the relationship between Abeta deposition and develop Abeta deposits and associated abnormalities at younger ages. These cohorts will be tested blindly and then sacrificed for neuropathological/neurochemical analysis (data provided by Project 2). Finally, a third line of Mo/Hu-APPswe mice (line Q2-2), which expresses the transgene at levels slightly less than required to induce Abeta deposition, will be behaviorally and neuropathologically/neurochemically analyzed. Our planned behavioral characterization of the mice, together with the neuropathological/neurochemical studies proposed in Project, will allow us to determine (with assistance in statistical analysis from Core B) the influence of APP hyper-expression, Abeta peptide synthesis, and Abeta deposition on the cognitive abilities of mice.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Aging (NIA)
• Type: Specialized Center (P50)
• Project #: 2P50AG005146-17
• Application #: 6210909
• Study Section: Special Emphasis Panel (ZAG1-PCR-3 (J5))
• Project Start: 1984-09-28
• Project End: 2004-03-31
• Support Year: 17
• Fiscal Year: 1999

Institution

• Name: Johns Hopkins University
• DUNS #: 045911138
• City: Baltimore
• State: MD
• Country: United States
• Zip Code: 21218

Publications

Bouhrara, Mustapha; Reiter, David A; Bergeron, Christopher M et al. (2018) Evidence of demyelination in mild cognitive impairment and dementia using a direct and specific magnetic resonance imaging measure of myelin content. Alzheimers Dement 14:998-1004

Xiong, Yulan; Neifert, Stewart; Karuppagounder, Senthilkumar S et al. (2018) Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice. Proc Natl Acad Sci U S A 115:1635-1640

Nicolas, Aude (see original citation for additional authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron 97:1268-1283.e6

Wong, Dean F; Comley, Robert A; Kuwabara, Hiroto et al. (2018) Characterization of 3 Novel Tau Radiopharmaceuticals, 11C-RO-963, 11C-RO-643, and 18F-RO-948, in Healthy Controls and in Alzheimer Subjects. J Nucl Med 59:1869-1876

Kirson, Noam Y; Scott Andrews, J; Desai, Urvi et al. (2018) Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. J Alzheimers Dis 61:295-307

Varma, Vijay R; Oommen, Anup M; Varma, Sudhir et al. (2018) Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study. PLoS Med 15:e1002482

Zhou, Zilu; Wang, Weixin; Wang, Li-San et al. (2018) Integrative DNA copy number detection and genotyping from sequencing and array-based platforms. Bioinformatics 34:2349-2355

Soldan, Anja; Pettigrew, Corinne; Albert, Marilyn (2018) Evaluating Cognitive Reserve Through the Prism of Preclinical Alzheimer Disease. Psychiatr Clin North Am 41:65-77

Guerreiro, Rita; Ross, Owen A; Kun-Rodrigues, Celia et al. (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64-74

Bermudez, Camilo; Plassard, Andrew J; Davis, Taylor L et al. (2018) Learning Implicit Brain MRI Manifolds with Deep Learning. Proc SPIE Int Soc Opt Eng 10574: