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Email tmelnik1@jhmi.edu
Phone (410) 502-2819

Tatiana Melnikova, Ph.D.

Primary Appointment in Pathology


The main focus of our laboratory is the investigation of different animal models of Alzheimer's disease and the contribution of different Aβ species to the development of behavioral and cognitive deficits during disease progression. By using different experimental treatments or genetic manipulations to alter Aβ production, we analyze the reversibility of the cognitive deficits at different stages of disease. Animal models of familiar form of Alzheimer’s disease include conventional transgenic mouse models (APPswe,PS1dE9; APPswe/PS1dE9/Cox2, etc) and conditional mouse models ( APPsi:tTA). In the latter APP production is driven by a tetracycline transactivator expressed in the brain areas involved in learning and memory. The overexpression of APP transgene is modulated by tetracycline analog, doxycycline (DOX). In our recent study we demonstrated that acute suppression of new APPsi/Aβ production in the APPsi:tTa mice with high levels of plagues accumulation significantly improved performance in short-term spatial memory tasks. These changes upon continued suppression were transformed in further improvement in more demanding tasks that assess long-term spatial and working memories. However, deficits in episodic –like memory and cognitive flexibility were more persistent and were still present after three weeks of DOX treatment as well as high plaques burden. Cognitive improvements coincided with dramatic reduction of different APP metabolites (full-length APP, soluble APP ectodomains, and APP C-terminal fragments) at the end of experiment. Despite the fact that animal models couldn’t recapitulate all aspects of the human disease they allow us to dissect different stages of disease progression and define the sensitive periods when it is still possible to delay or reverse cognitive deficits.

In other projects we are looking at the pathogenic mechanisms involved in autism spectrum disorder and investigating the pathways implicated in schizophrenia-like endopenotypes. In particularly, we are studying BACE1- dependent NRG1-ErbB4 signaling interactions with glutamatergic receptors pathways. We found that the mice with deletion of BACE1 (-site APP cleavage enzyme1) exhibited multiple behavioral endophenotypes related to schizophrenia such as deficits in prepulse inhibition, novelty-induced hyperactivity, sensitivity to a psychostimulant, disturbances in social interactions, and cognitive deficits. We continue this work by testing the hypothesis that changes in BACE1/NRG1 signaling could be primary or secondary to the alterations in glutamatergic mechanisms implicated in schizophrenia. To this end, we compare two different models of schizophrenia. As a first model, we are using BACE1 knockout mice, in which changes in BACE1/NRG1 signaling are primary. In the second model we are using PCP treatment during early development that results in primary alterations in glutamatergic pathway.

Publications

Jankowsky JL, Melnikova T, Fadale DJ, Xu GM, Slunt HH, Gonzales V, Younkin LH, Younkin SG, Borchelt DR, Savonenko AV. Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease. The Journal of Neuroscience. 2005; 25: 5217-5224.

Savonenko AV, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong M, Price D L, Tang F, Markowska AL, Borchelt DR. Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationship to β-amyloid deposition and neurotransmitter abnormalities. Neurobiology of Disease. 2005; 18: 602-617.



 


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