Dementia is defined as cognitive loss severe enough to affect daily living and unlike other leading causes of death, the number of persons afflicted with dementia is increasing. The two most common forms of dementia are Alzheimer's disease (AD) and vascular contributions to cognitive impairment and dementia (VCID). Although they have different etiologies, these two forms of dementia share some similar pathologies such as vasogenic edema and microhemorrhages. These pathologies were also exacerbated when anti- amyloid beta (A?) immunotherapy was used for treatment of AD causing termination of the clinical trials. Matrix metalloproteinases (MMPs) are proteases that can break down the blood brain barrier leading to vasogenic edema and microhemorrhage. The specific goals of this proposal are to determine the contribution of two specific MMPs, MMP2 and MMP9, to the occurrence of vasogenic edema and microhemorrhage, and to evaluate whether the presence of VCID will reduce the efficacy of anti-A? treatment. The overall goal of this proposal is to provide possible targets for adjunct therapies with anti-A? immunotherapy and improve AD clinical trials by screening for VCID co-morbidities. To achieve these goals, this proposal will utilize in vivo (Aim 1) and in vitro (Aim 2) methods.
In Aim 1, the effect of VCID on the efficacy f anti-A? immunotherapy, vasogenic edema, and microhemorrhages will be determined. Transgenic mice with amyloid deposition will be placed on the hyperhomocysteinemia diet to induce VCID and then treated with an anti-A? immunotherapy. When VCID is pre-existing in a model of amyloid deposition, treatment with anti-A? immunotherapy will increase activation of the MMP2 and MMP9 systems, exacerbate microhemorrhages and vasogenic edema, and have reduced efficacy on cognition. Vasogenic edema, microhemorrhages, cognitive changes and MMP2 and MMP9 activity will be determined for Aim 1.
Aim 2 will evaluate the role of MMP9 in the degradation of tight junctions in endothelial and astrocyte co-culture. The effect of inhibitio of MMP9 on tight junction degradation will also be assessed. Inflammatory- mediated activation of MMP9 will degrade tight junctions between cerebrovascular endothelial cells leading to vasogenic edema and microhemorrhages and inhibition of MMP9 will reduce tight junction degradation. Tight junction permeability and MMP9 activity will be assessed for Aim 2. Together these aims will offer valuable information on the contribution of MMP2 and MMP9 to vasogenic edema and microhemorrhage occurrence, and the effect VCID has on anti-A? immunotherapy. These studies will provide training in new techniques. Specifically, the applicant will learn how t execute cell biology based assays such as the sodium fluorescein assay and the isolation of primary astrocytes along with data analysis and interpretation skills.
These aims and the training potential provided by them will aid the applicant in achieving their long term career goals.
Alzheimer's disease and vascular contributions to cognitive impairment and dementia (VCID) are the two most common forms of dementia affecting 55% and 20% of dementia patients, respectively. This proposal is designed to offer valuable information on the contribution of specific proteins to pathologies common to Alzheimer's disease and VCID (vasogenic edema and microhemorrhage), and the effect VCID has on therapies for Alzheimer's disease (anti-A? immunotherapy). With this information, we will provide possible targets for adjunct therapies with anti-A? immunotherapy and improved clinical trials of Alzheimer's disease by screening more closely for patients with VCID co-morbidities.
| Sudduth, Tiffany L; Weekman, Erica M; Price, Brittani R et al. (2017) Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID). Neuroscience 341:42-51 |
| Weekman, Erica M; Sudduth, Tiffany L; Caverly, Carly N et al. (2016) Reduced Efficacy of Anti-A? Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity. J Neurosci 36:9896-907 |
