Ongali_2010_Am.J.Pathol_177_3071

High brain levels of amyloid-beta (Abeta) and transforming growth factor-beta1 (TGF-beta1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in Abeta and TGF-beta1 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, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular Abeta deposition, astrocyte activation, and impaired Morris water maze performance, which gained severity with age. The combined Abeta- and TGF-beta1-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 Abeta and TGF-beta1 increments.