Abstract
Peptides derived from proteolytic processing of the beta-amyloid precursor protein (APP), including the amyloid-beta peptide (Abeta), play a critical role in the pathogenesis of Alzheimer's dementia. We report that transgenic mice overexpressing APP and Abeta have a profound attenuation in the increase in neocortical blood flow elicited by somatosensory activation. The impairment is highly correlated with brain Abeta concentration and is reproduced in normal mice by topical neocortical application of exogenous Abeta1-40 but not Abeta1-42. Overexpression of M146L mutant presenilin-1 in APP mice enhances the production of Abeta1-42 severalfold, but it does not produce a commensurate attenuation of the hyperemic response. APP and Abeta overexpression do not diminish the intensity of neural activation, as reflected by the increase in somatosensory cortex glucose usage. Thus, Abeta-induced alterations in functional hyperemia produce a potentially deleterious mismatch between substrate delivery and energy demands imposed by neural activity.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amyloid beta-Peptides / biosynthesis
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Peptides / pharmacology
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Cerebrovascular Circulation* / drug effects
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Female
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Glucose / metabolism
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Humans
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Hypercapnia / metabolism
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Hypercapnia / physiopathology
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Hyperemia / metabolism
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Hyperemia / physiopathology
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Laser-Doppler Flowmetry
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / genetics
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Peptide Fragments / biosynthesis
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Peptide Fragments / genetics
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Peptide Fragments / metabolism*
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Peptide Fragments / pharmacology
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Physical Stimulation
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Presenilin-1
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Somatosensory Cortex / blood supply*
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Somatosensory Cortex / drug effects
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Somatosensory Cortex / metabolism*
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Somatosensory Cortex / physiology
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Touch / physiology
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Vibrissae / physiology
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Membrane Proteins
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PSEN1 protein, human
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Peptide Fragments
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Presenilin-1
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Glucose