Alzheimer's disease (AD) is a multi-factorial neurodegenerative disorder. According to the prevailing amyloid cascade hypothesis, cognitive decline and distinct pathogenic features in AD relate to abnormal accumulation of amyloid beta-peptide (A?) in the brain. While efforts are underway to enhance A? clearance, prevent its formation, or to develop anti- A? small molecules, recent evidence implicates neurovascular dysfunction and compromised cerebral blood flow (CBF) in the pathogenesis of AD. Based on published data derived from our Phase I application and novel preliminary data provided herein, we seek to pharmacologically undermine enhanced activity of two transcription factors, serum response factor (SRF) and myocardin (MYOCD), in cerebral vascular smooth muscle cells (VSMC) derived from patients with AD. SRF/MYOCD constitute a potent transcriptional switch for a VSMC contractile gene program, which is exaggerated in AD-VSMC and coincides with a hypercontractile phenotype leading to reduced CBF in mouse models of AD. Moreover, new preliminary data support SRF/MYOCD in defective A? clearance by VSMC and the expression of LRP1, which is a major mediator of A? elimination via the circulation. Together, these data lead us to formulate the following hypothesis: elevated SRF/MYOCD activity in AD VSMC leads to a hypercontractile phenotype in small cerebral arteries and the accumulation of A? which contribute to CBF reductions and neurovascular uncoupling as seen in A?, whereas drugs which specifically block MYOCD interaction with SRF will """"""""unlock"""""""" the hypercontractile/ A? AD VSMC phenotype, improve CBF and alleviate symptoms of dementia.
The specific aims designed to test this hypothesis include (1) validating novel small molecule inhibitors of SRF/MYOCD we have identified through library screening; (2) evaluating lead compounds for their ability to normalize VSMC hypercontractility and A? clearance in vitro; and (3) evaluating lead compounds for their ability to normalize VSMC hypercontractility, A? clearance, and behavioral deficits in a novel mouse model of AD phenotype we have recently developed. These innovative and highly robust studies are expected to uncover a new class of potential AD therapeutics that should be poised well for further toxicity and preclinical trials, thus providing impetus for their assessment in normalizing the cerebrovascular dysregulation and neurovascular uncoupling associated with AD and dementia. Currently, there are no effective therapies to prevent or reverse the inexorable course of Alzheimer's disease (AD) and associated dementias. A common thread amongst such neurodegenerative diseases is a compromise in blood flow to the brain. This application seeks to evaluate a potential new class of therapeutics designed to disrupt two proteins shown to be hyperactive in blood vessels of the brain of AD patients. ? ? ?
| Imamura, Masaaki; Long, Xiaochun; Nanda, Vivek et al. (2010) Expression and functional activity of four myocardin isoforms. Gene 464:1-10 |
| Bell, Robert D; Deane, Rashid; Chow, Nienwen et al. (2009) SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol 11:143-53 |
