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Alzheimer's Disease Research - Alena Savonenko, M.D., Ph.D.

Noradrenalinergic deficits as disease-modifying targets in AD mouse models

Through a Pilot Project grant provided by the Johns Hopkins Alzheimer's Disease Research Center, Dr. Savonenko is investigating whether increasing the levels of NE via pharmacological treatment with uptake inhibitors can attenuate cognitive and non-cognitive behavior abnormalities associated with amyloid deposition and neurodegeneration in APPswe/PS1dE9 Tg mice. These studies will be very important in delineating mechanisms of cognitive/behavioral deficits in AD and may support the use of NE uptake inhibitors as therapeutic agents for AD.

The clinical syndrome of Alzheimer Disease (AD) is associated with cerebral amyloid deposition and the dysfunction/death of neurons in multiple brain regions and cognitive and behavioral dysfunctions. While the general view is that production of Aβ is mechanistically associated with neurodegeneration in AD, the in vivo relationship between Aβ and neurodegeneration is not fully understood. Currently, study of neurodegeneration in the transgenic mouse models (Tg) of cerebral Aβ deposition has been limited because they do not show robust degeneration of cortical and hippocampal neurons. However, we have found that cerebral Aβ deposition in a line of APPswe/PS1ΔE9 Tg mice is associated with a progressive degeneration of monoaminergic neurons, recapitulating degeneration of serotoninergic (5-HT) and noradrenergic (NE) neurons in human AD. Degeneration of these neurons and their respective axonal projections may play a role in AD-associated dysfunctions related to learning, memory and affect.

In this investigation, we will test causative relations between monoaminergic neurodegeneration and cognitive decline in APPswe/PS1ΔE9 Tg model by using pharmacological treatment with 5-HT/NE uptake inhibitors. The study is specifically designed to evaluate the efficacy of these treatments on different stages of monoaminergic neurodegeneration that is a nessesary step in predicting a "window of opportunity" for effective clinical treatment.