Transgenic Mice Overexpressing APP and Transforming Growth Factor-β1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease

High brain levels of amyloid beta (A beta) and transforming growth factor beta 1 (TGF beta 1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer s disease (AD) We sought to investigate the Impact of combined increases in A beta and TGF beta 1 on cerebrovascular neuronal and mnemonic function using transgenic mice overproducing these peptides A/T mice) In particular, we measured cerebrovascular reactivity evoked cerebral blood flow and glucose uptake during brain activation cholinergic status and spatial memory along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age An assessment of perfusion and metabolic responses was considered timely given ongoing efforts for their validation as AD) biomarkers Relative to wild type littermates A/T mice displayed an early progressive decline in cerebrovascular dilatory ability preserved contractility and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone Altered levels of vasodilator synthesizing enzymes and fibrotic proteins resistance to antioxidant treatment and unchanged levels of the antioxidant enzyme super oxide dismutase 2 accompanied these impairments A/T mice featured deficient neurovascular and neuro metabolic coupling to whisker stimulation cholinergic denervation cerebral and cerebrovascular A beta deposition astrocyte activation and impaired Morris water maze performance which gained severity with age The combined A beta and TGF beta 1 driven pathology recapitulates salient cerebrovascular neuronal and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring A beta and TGF beta 1 Increments (Am J Pathol 2010 177 3071-3080 DOI 10 2353/ajpath 2010 100339)