The neuropathological features of Alzheimer's disease are characterized by the presence of insoluble amyloid deposits in the brain and cerebrovasculature, the intra-neuronal accumulation of abnormally phosphorylated and aggregated forms of tau, a microtubule binding protein and neuronal loss. Although the exact mechanisms producing these pathological changes remain unknown, the amyloid cascade hypothesis states that the peptides (Ass) that make up amyloid deposits are the cause of the disease process. Despite numerous supportive studies, discrepancies between animal models of AD and humans with AD remain an obstacle for full acceptance of Ass as the primary causal agent for AD. By altering the nitric oxide in mouse brain, we have generated a novel mouse model that provides unique insights into mouse-human differences. Our bigenic mouse models of AD increase the expression of human Ass on a murine nitric oxide synthase 2 (NOS2) knockout background. The resulting phenotype is highly reminiscent of the pathology observed in humans with AD including high levels of Ass peptides, tau hyperphosphorylation, tau redistribution and tau aggregation, neuronal loss and behavioral deficits. A primary advantage of the APPSw/NOS2-/- mouse is the formation of tau pathology from normal, not mutated tau AND the presence of significant neuronal loss. Thus, our model provides a unique opportunity to fully test the amyloid cascade hypothesis in vivo under conditions of chronic disease.
The first aim will confirm a pathological cascade in the APPSw/NOS2-/- mouse brain by measuring Ass, tau pathology, neuronal loss and memory and learning in the APPSw/NOS2-/- mice brains at specific ages. To establish a direct, causal role for Ass peptides in the cascade, we propose a) to reduce Ass levels in the brains of APPSw/NOS2-/- mice by passive immunization and b) to increase Ass levels in the brains of NOS2-/- mice using intrahippocampal injection of Ass peptide mixtures.
The second aim will examine the role of NOS2. We propose a) to reduce brain iNOS protein using lentivirus delivery of small interfering RNA (shNOS2 lentivirus) b) to test the ability of NOS2 and NO replacement to alter the pathological cascade mediated by Ass.
The third aim will examine a likely mechanism of NO's action, the regulation of caspase activity.
This project will examine the role of Abeta peptides derived from the amyloid precursor protein in generating the neuropathology associated with chronic neurodegenerative diseases such as Alzheimer's disease. The method used will involve the generation of a novel mouse model for potential therapeutic value and will provide a useful to tool to fully investigate therapeutics in the pre-clinical stage.
|Kan, Matthew J; Lee, Jennifer E; Wilson, Joan G et al. (2015) Arginine deprivation and immune suppression in a mouse model of Alzheimer's disease. J Neurosci 35:5969-82|
|Colton, Carol A; Wilson, Joan G; Everhart, Angela et al. (2014) mNos2 deletion and human NOS2 replacement in Alzheimer disease models. J Neuropathol Exp Neurol 73:752-69|
|Hoos, Michael D; Richardson, Brenna M; Foster, Matthew W et al. (2013) Longitudinal study of differential protein expression in an Alzheimer's mouse model lacking inducible nitric oxide synthase. J Proteome Res 12:4462-77|
|Ridnour, Lisa A; Dhanapal, Sneha; Hoos, Michael et al. (2012) Nitric oxide-mediated regulation of Î²-amyloid clearance via alterations of MMP-9/TIMP-1. J Neurochem 123:736-49|
|Wilcock, Donna M; Zhao, Qun; Morgan, Dave et al. (2011) Diverse inflammatory responses in transgenic mouse models of Alzheimer's disease and the effect of immunotherapy on these responses. ASN Neuro 3:249-58|
|Shineman, Diana W; Basi, Guriqbal S; Bizon, Jennifer L et al. (2011) Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies. Alzheimers Res Ther 3:28|
|Wilcock, Donna M; Morgan, Dave; Gordon, Marcia N et al. (2011) Activation of matrix metalloproteinases following anti-AÎ² immunotherapy; implications for microhemorrhage occurrence. J Neuroinflammation 8:115|
|Wink, David A; Hines, Harry B; Cheng, Robert Y S et al. (2011) Nitric oxide and redox mechanisms in the immune response. J Leukoc Biol 89:873-91|
|Van Nostrand, William E; Xu, Feng; Rozemuller, Annemieke J M et al. (2010) Enhanced capillary amyloid angiopathy-associated pathology in Tg-SwDI mice with deleted nitric oxide synthase 2. Stroke 41:S135-8|