Assistant Professor - Department of Neuroscience Assistant Professor - Department of Neurosurgery Ph.D., California Institute of Technology, 1999 One Baylor Plaza Baylor College of Medicine Houston TX, 77030 Telephone: 713-798-8337 - Fax: 713-798-3946 Email: jjankowsky@cns.bcm.edu

The goal of our research is to understand how the abnormal accumulation of a small peptide known as Aβ leads to the overwhelming cognitive decline of Alzheimer's disease. Implicit in our work is the idea that by understanding the relationship between Aβ and Alzheimer's we will be able to design therapeutic strategies that disconnect their coupling to treat the disease. Our laboratory uses transgenic mice to explore how the presence of excess Aβ impacts the brain at levels ranging from individual neurons to complex behavior, using techniques of classic histology, electrophysiology, and cognitive testing. Current work focuses on a novel line of transgenic mice in which expression of the amyloid precursor protein, from which Aβ is derived, is controlled by a tetracycline-responsive promoter. This system allows us to study how the disease responds once the production of Aβ is blocked. Work so far has shown that this intervention stops the accumulation of Aβ into insoluble amyloid plaques, but that deposits formed prior to treatment will remain for life. Our goal now is to understand what level of functional recovery is possible while the pre-existing plaques remain in place, and whether a combination of therapies that remove residual aggregates will provide greater benefit.

A second avenue of research in the laboratory explores the role of individual cell populations and circuits in the cognitive decline of Alzheimer's disease. Based on recent work in mouse models and decades of human neuropathology, we know which areas of the brain degenerate in Alzheimer's patients, and relatively speaking, in what chronological order. Our goal is to understand how the sequential loss of these neuronal populations causes the progressive symptoms of Alzheimer's. For this work we will develop transgenic mice expressing a chloride channel that selectively responds to a common anti-parasitic drug. On exposure to the drug, neurons expressing the channel become hyperpolarized, temporarily disengaging them from their normal circuit and reproducing how their loss would alter brain function in patients with Alzheimer's disease. The first neuronal population we will target is in the hippocampus, an area critical for learning and memory, where we have shown that the survival of adult-born neurons is significantly reduced in mice overproducing Aβ. By its design, the silencer mouse will allow us to study the function of any population of neurons for which we can identify a specific promoter and an appropriate behavioral measure. Long-term, we will apply this strategy to other circuits affected in Alzheimer's disease such as the basal forebrain cholinergic system and the entorhinal cortex, with the goal of elucidating how loss of each contributes to the disease.

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Verret L.*, Jankowsky J.L.*, Xu G., Borchelt D.R., and Rampon C. (2007) Alzheimer's-type amyloidosis in mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis. J. Neurosci. 27:6771-6780

Jankowsky J.L., Younkin L.H., Gonzales V., Fadale D.J., Slunt H.H., Lester H.A., Younkin S.G., and Borchelt D.R. (2007) Rodent Aβ modulates the solubility and distribution of amyloid deposits in transgenic mice. J. Biol. Chem. 282:22707-22720

Jankowsky J.L., Melnikova T., Fadale, D.J., Xu, G.M., Slunt, H.H., Gonzales, V., Younkin, L.H., Younkin, S.G., Borchelt, D.R., and Savonenko, A.V. (2005) Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease. J. Neurosci. 25:5217-5224 

Jankowsky J.L., Slunt, H.H., Gonzales, V., Savonenko, A.V., Wen, J., Jenkins, N.A., Copeland, N.G., Younkin, L.H., Lester, H.A., Younkin, S.G., and Borchelt, D.R. (2005) Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer's disease.  PLoS Medicine 2:e355

Jankowsky J.L., Fadale, D.J., Anderson, J., Xu, G., Gonzales, V., Jenkins, N.A., Copeland, N.G., Lee, M.K., Younkin, L.H., Wagner, S.L., Younkin, S.G., and Borchelt, D.R. (2004) Mutant presenilins specifically elevate the levels of the 42-residue β-amyloid peptide in vivo:  evidence for augmentation of a 42-specific g-secretase. Hum. Mol Genet. 13:159-170

Jankowsky, J.L., Slunt, H.H., Gonzales, V., Jenkins, N.A., Copeland, N.G., and Borchelt, D.R. (2004) APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1. Neurobiol. Aging 25:885-892

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NIH Director's New Innovator Award (DP2; 2007-2012)

NIH Mentored Research Scientist Award (K01; 2004-2009)

NARSAD Young Investigator Award (2004-2006)

John Douglas French Alzheimer's Foundation Fellow (2001-2003)

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• Heather Born (Neuroscience)

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Immunostaining for Aβ reveals progressive accumulation of amyloid plaques (brown) throughout the forebrain of tet-off APP mice. Initial amyloid deposits can be seen in the cortex, hippocampus, and olfactory bulb as early as 2 months of age in this highly overexpressing transgenic model; pathology worsens significantly with time. Using tetracycline to block APP expression, we have shown that suppressing Aβ keeps the pathology from getting worse, but amyloid formed prior to treatment remains in place. Future work will determine whether the presence of residual plaques limits functional recovery in treated animals, and if so, whether a combination of therapies capable of removing pre-existing plaques provides greater benefit.

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