Aβ1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation

Peptides derived from proteolytic processing of the beta-amyloid precursor protein (APP), including the amyloid-beta peptide (A beta), play a critical role in the pathogenesis of Alzheimer's dementia. We report that transgenic mice overexpressing APP and A beta have a profound attenuation in the increase in neocortical blood flow elicited by somatosensory activation. The impairment is highly correlated with brain A beta concentration and is reproduced in normal mice by topical neocortical application of exogenous A beta 1-40 but not A beta 1-42. Overexpression of M146L mutant presenilin-1 in APP mice enhances the production of A beta 1-42 severalfold, but it does not produce a commensurate attenuation of the hyperemic response, APP and A beta overexpression do not diminish the intensity of neural activation, as reflected by the increase in somatosensory cortex glucose usage. Thus, A beta-induced alterations in functional hyperemia produce a potentially deleterious mismatch between substrate delivery and energy demands imposed by neural activity.