Reversing Alzheimer’s Disease-Associated Impairments of Synaptic Plasticity and Memory by Targeting AMP-Activated Protein Kinase

Currently, more than five million Americans have Alzheimer’s disease (AD), and the number is estimated to rise dramatically in the next few decades. Unfortunately, until now, there is no therapy or drug available to cure or slow down the process of AD. In this study, Dr. Ma will determine the role of an important signaling pathway (5′ AMP-activated protein kinase or AMPK) in the development and progression of AD, and potentially translate these discoveries into novel therapeutic targets for AD and related cognitive syndromes.

There are three specific aims in this study. In the first aim, Dr. Ma is studying brain samples donated by deceased human AD patients, as well as brain samples from established mouse models of AD. This data should provide details on how AMPK and its associated signaling pathways are regulated in AD. The second and third specific aims focus on determining how restoring abnormal AMPK signaling improves AD-associated learning and memory defects, including impairments of “synaptic plasticity” (chemical and physical changes in the connections between nerve cells).

In the second aim, both drugs (small molecule inhibitors) and genetics (genetically engineered mice) are being used to determine whether AD-related deficits of long-term potentiation (LTP) or long-term depression (LTD), two primary forms of “synaptic plasticity,” can be rescued by normalizing AMPK signaling. In the third aim, two behavioral tasks widely used to assess performance of memory are being used to determine how memory deficits in AD can benefit from restoration of AMPK signaling.

Current disease-modifying strategies in clinical trials mostly focus on lowering levels of brain beta-amyloid (Abeta), and have had limited success. It is clearly urgent and necessary to identify alternative therapeutic targets to cure AD. Dr. Ma’s project incorporates multiple approaches, including many state-of-the-art techniques, to investigate in detail an Abeta-independent treatment for Alzheimer’s disease.

When this study is complete it will offer significant insights into the very core of the processes involved with Alzheimer’s disease that may be translated into developing novel therapies for this devastating disease. Dr. Ma and his team are thrilled to be part of the development, and can not sufficiently express their gratitude to those willing to support this work.