There are currently no effective treatments to prevent, delay, or reverse the memory deficits and neuropathological alterations?specifically dendritic damage and synaptic loss?associated with Alzheimer?s disease (AD). Without an effective treatment soon, many more millions of older adults will continue to suffer from this devastating disease. Thus, there is a critical need to investigate novel molecules/mechanisms involved in the maintenance and regeneration of dendrites and their spines for the purpose of rescuing cognitive functions. The long-term goal is to develop an effective treatment to prevent or halt AD. The overall objective of this application is to determine the potential of a recently identified phosphoprotein, CRMP3 (collapsing response mediator protein 3), to ameliorate dendritic abnormalities and/or rescue memory deficits in two distinct mouse models with AD-like characteristics. 3xTg-AD mice are one of the most commonly used mouse models of AD. They harbor 3 mutations (APP, PSEN1, and MAPT) that result in the accumulation of plaques and tangles, abnormalities in dendritic and synaptic structures, and significant cognitive impairments. CRMP3-/- mice exhibit dystrophic hippocampal dendrites and profoundly impaired synaptic plasticity (LTP). Importantly, overexpressing the CRMP3 protein in hippocampal neurons, in vitro, dramatically enhances dendritic formation. The central hypothesis is that over-expressing CRMP3, in vivo, will prevent further dendritic degeneration and/or evoke dendritic regrowth and remodeling of spines in otherwise degenerating hippocampal neurons, thus preserving or rescuing memory function. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicants? laboratories. This hypothesis will be tested by pursuing two specific aims: 1) Determine the extent to which in vivo over-expression of CRMP3 enhances hippocampal dendritic complexity and spine structure in CRMP3-/- and 3xTg-AD mice; and 2) Determine the extent to which in vivo over-expression of CRMP3 affects hippocampal-dependent memory function in CRMP3-/- and 3xTg-AD mice. Under the first aim, adeno-associated viral vector serotype 9 (AAV9) gene therapy will be used to overexpress CRMP3 in the hippocampus of these two AD-like mouse models and its effects on AD-associated spino-dendritic abnormalities will be examined. Under the second aim, the extent to which CRMP3 gene therapy can ameliorate contextual and spatial memory function will be measured using two behavioral paradigms (contextual fear conditioning and Morris water maze). The approach is innovative because CRMP3 is a little-known protein with tremendous potential to repair and regenerate dystrophic and damaged spines and dendrites. The proposed research is significant because it is expected to advance knowledge about a protein with the robust capacity to slow, halt, or even reverse early AD processes that may be precursors to deep dementia, thus profoundly improving quality of life. Ultimately, such findings have the potential to move to clinical trials as a treatment for AD.
The proposed research is relevant to public health because it will determine the extent to which CRMP3 gene therapy can rejuvenate dendrites and spines and prevent memory deficits in AD- like mouse models. If successful, this work could easily transition to AD clinical trials. Consistent with the mission of the NIH, to develop new classes of therapeutics for Alzheimer?s disease, it is expected to have a positive impact on the treatment of Alzheimer?s disease as well as other neurodegenerative diseases which would profoundly improve quality of life.
