Peptides derived from proteolytic processing of the ␤-amyloid precursor protein (APP), including the amyloid-␤ peptide (A␤), play a critical role in the pathogenesis of Alzheimer's dementia. We report that transgenic mice overexpressing APP and A␤ have a profound attenuation in the increase in neocortical blood flow elicited by somatosensory activation. The impairment is highly correlated with brain A␤ concentration and is reproduced in normal mice by topical neocortical application of exogenous A␤1-40 but not A␤1-42. Overexpression of M146L mutant presenilin-1 in APP mice enhances the production of A␤1-42 severalfold, but it does not produce a commensurate attenuation of the hyperemic response. APP and A␤ overexpression do not diminish the intensity of neural activation, as reflected by the increase in somatosensory cortex glucose usage. Thus, A␤-induced alterations in functional hyperemia produce a potentially deleterious mismatch between substrate delivery and energy demands imposed by neural activity.Alzheimer's disease͞␤-amyloid͞cerebral blood flow͞functional activation T he amyloid precursor protein is closely linked to the pathogenesis of Alzheimer's dementia (AD; refs. 1 and 2). Mutations in all three early onset familial AD genes, the amyloid precursor protein (APP), presenilin-1 (PS1), and 2 (PS2), cause elevation of APP-derived A␤ peptides that accumulate in the brain parenchyma and blood vessels (3-5). These observations, collectively, have led to the hypothesis that A␤ peptides are intimately involved in the pathogenesis of AD. Furthermore, transgenic mice overexpressing APP have increased levels of A␤ in brain, and transgenic lines expressing high levels of mutant APP develop some of the pathological and behavioral hallmarks of AD (6).The mechanisms by which A␤ contributes to neuronal dysfunction and neurodegeneration in AD have not been elucidated. Although most studies have focused on the effects of A␤ on neurons, recent evidence suggests that A␤ has profound effects on cerebral blood vessels as well (7-10). Patients with AD have morphological alterations of the cerebral vasculature and reduced cerebral blood flow (CBF), and mice overexpressing APP have a marked impairment in the response of cerebral blood vessels to exogenous vasoactive agents (9-12). However, the impact that these cerebrovascular alterations have on the regulation of the cerebral circulation remains to be defined. Neural activity is one of the major factors regulating CBF (13). Thus, CBF is closely matched to the energy requirements of the brain (14-17). If a brain region is activated, blood flow to that region increases to facilitate local delivery of nutrients and to remove metabolic waste (13). Here we report that APP and A␤ overexpression impairs the increase in neocortical CBF produced by physiological activation of the somatosensory pathway and causes a potentially-deleterious mismatch between blood flow and cerebral energy consumption. MethodsTransgenic Mice. All transgenic lines used in these studies have been described...

Different prion Isolates, often referred to as "strains," present an enigma because considerable evidence argues that prions are devoid of nucleic acid. To investigate prion diversity, we inoculated three "strains" of prions into congenic and transgenic mice harboring variable numbers of two dierent alleles, designated a and b, of the prion protein (rP) structural gene, Prn-p. The length of the incubation time was inversely related to the number of Pm-p genes in mice inoculated with the Rocky Mountain Laboratory (RML) prion strain. Results with mice lacking this locus (Prnpe/) and ransgenic mice argue that long incubation times are not a dominant trait as thought for many years, but rather they are due to reduced levels of the substrate PrPC-A (cellular isoform of PrP, allotype A) in (Prn-p5 x Pvn-pb)Fi mice. In contrast, the Prn-pa gene extended incubation times in mice inoculated with the 87V and 22A prion strains, whereas the Prm-pb gene was permissive. Experiments with the 87V Isolate suggest that a genetic locus distinct from Prn-p controls deposition of the scraple isoform of PrP (Prs) and attendant neuropathology.Each prion isolate produced di hable patterns of PrPsc accumulation in brain; of note, the patterns in Prn-pa and Prn-pb congenic mice inculated with RML prions were more different than those in congenic Prn-9b mice with RML or 22A prions. Our results suggest that scrapie "strain-specific" incubation times can be explained by differences in the relative efficiency of allotypic interactions that lead to conversion of PrPC Into prPsc.

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