An understanding of Alzheimer's disease (AD) etiology and evaluation of potential therapeutic modalities is critically dependent upon animal models of the disease. The utility of current non-inducible animal models of AD is limited, due to 1) possible developmental effects of transgene overexpression from birth which could influence AD-like pathology, and 2) inability to turn transgene expression """"""""off"""""""" in adult animals to determine the effect of transgene inactivation on AD-like pathology. The focus of this proposal is to address these issues by establishing a transgenic mouse model of AD that overexpresses mutant human amyloid precursor protein (mhAPP) under the tetracycline (tat) regulated system.
In specific aim 1, a construct containing a tetO responsive promoter and a mutant human APP cDNA (tetO-mhAPP) will be generated and validated.
In specific aim 2, mice (designated Tet/mhAPP) that conditionally express mhAPP in the forebrain under tat regulatory control will be generated.
Specific aim 3 will investigate the kinetics of AD-like pathology in Tet/mhAPP mice in which transgene expression is induced postnatally. Finally, in specific aim 4, possible reversal of AD-like pathology will be examined by blocking mhAPP expression in aged mice with established AD-like pathology.
