I lead a collaborative and interinstitutional research program that uses a multidisciplinary approach to identify early causative events underlying ‘normal’ nonpathological age-related memory decline and Alzheimer’s dementia.
What causes the dramatic variation in “normal” cognitive aging and the disease-related mental decline observed in Alzheimer’s? The work in my laboratory seeks to answer this question by identifying the complex set of factors that explain why some individuals are “resilient” to aging and cognitive disease, while other people can succumb to these destructive changes in middle age. The question is not new, but it remains unanswered, in part because the answer will not be a simple one, but also because all of the tools needed to dissect the underlying complexity were not previously available. My lab has developed key paradigms and strategies that, in combination with other state-of-the-art molecular, genomic and analytical approaches, have positioned us to make significant new biological insights, identify potential predictive biomarkers, and ultimately to identify and initiate development of new treatments.
My collaborative, interinstitutional research program takes a multidisciplinary approach to attack the problem on multiple fronts simultaneously. Our extensive collaborative interactions expand both the scope and impact of our work and offer lab members a variety of complementary training opportunities. One such collaboration is focused on creation of mouse models that better reflect the complexity of Alzheimer’s Disease-Related Dementias by “designing” mice that display pathologies produced by complex interactions between genetic and environmental influencesIn a related and integrated effort our group is also directly involved in the JAX Center for Alzheimer’s and Dementia Research that is using state-of-the-art computational approaches for genomic analysis and molecular engineering to “build” predictive mouse models that better emulate the human disease.
We have expertise that encompasses and integrates systems genetics with in vivo and in vitro electrophysiological recording, proteomics, viral-based gene transduction and sophisticated analytical/computational genomic techniques, including single nuclear sequencing. Ongoing projects are designed to address different aspects of our central question and are funded both through NIH grants as well as by private foundations such as the Alzheimer’s Association.
Ouellette A., Neuner, S, Dumitrescu, L., Anderson, L., Gatti, D., Mahoney, E., Bubier, J., Churchill, G., Peters, L., Huentelman, M., Herskowitz, J., Yang, H., Smith, A., Reitz, C., Kunkle, B., White, C., De Jager, P., Schneider, J., Bennett, D., Seyfried, N., Chesler, E., Hadad, N., Hohman, T., Kaczorowski, C. C., Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer's Dementia. Cell Rep DOI: 10.1016/j.celrep.2020.108091
Neuner, S.M., Heuer, S., Huentelman, M., O’Connell, K. and Kaczorowski, C.C. (2019) Harnessing genetic complexity to enhance Alzheimer’s disease mouse models: a path towards experimental precision medicine. Neuron doi:10.1016/j.neuron.2018.11.040
Dunn, A.R., O’Connell, K.*, Kaczorowski, C.C.* (2019) Gene-by-environment interactions in Alzheimer’s disease and Parkinson’s disease. Neuroscience & Biobehavioral Reviews, 103:73-80. doi.org/10.1016/j.neubiorev.2019.06.018; * denotes co-senior authors
Neuner, S.M., Ding, S., and Kaczorowski, C.C. (2019) Knockdown of heterochromatin protein 1 binding protein 3 recapitulates phenotypic, cellular, and molecular features of aging. Aging Cell, doi:10.1111/acel.12886
Neuner, S.M., Garfinkel, B.P., Wilmott, L., Ignatowska-Jankowska, B., Citri, A., Orly, J., Lu, L., Overall, R.W., Mulligan, M., Kempermann, G., Williams, R.W., O’Connell, K.M., and Kaczorowski, C.C. (2016) Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging. Neurobiology of Aging.
Neuner, S.M., Heuer, S., Zhang, J., Philip, V., and Kaczorowski, C.C. (2019) Identification of pre-symptomatic gene signatures that predict resilience to Alzheimer’s disease. Frontiers in Genetics, Special Topics Systems Genetics of Neurodegenerative Disease, doi:10.3389/fgene.2019.00035
Dunn, A.R.*, Neuner, S.M.*, Ding, S., Hope, K.A. O’Connell, K. and Kaczorowski, C.C. (2019) Cell-type specific changes in intrinsic excitability in the subiculum following novel experimental contexts and learning, eNeuro, doi.org/10.1523/ENEURO.0484-18.2018 * denotes co-first authors
Graves, A.R., Moore, S.J., Spruston, N., Tryba, A.K., Kaczorowski C.C. (2016) Brain derived neurotrophic factor differentially modulates excitability of two distinct classes of hippocampal output neurons. May 4th, Journal of Neurophysiology.
Neuner, S.M., Wilmott, L., Hope, K.A., Hoffmann, B., Chong, J.A., Abramowitz, J., Birnbaumer, L., O’Connell, K.M., Tryba, A.K., Greene, A.S., Chan., C.S., and Kaczorowski, C.C. (2015) TRPC3 channels critically regulate hippocampal neuron excitability and memory. Behavioural Brain Research, 281, 69-77
Dunn, A.R., Kaczorowski, C.C. (2019) Regulation of intrinsic excitability: Roles for learning and memory, aging and Alzheimer's disease, and genetic diversity. Neurobiology of Learning and Memory. doi.org/10.1016/j.nlm.2019.107069
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