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. 2000 Aug 15;97(17):9735-40.
doi: 10.1073/pnas.97.17.9735.

Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation

K Niwa  1 , L Younkin, C Ebeling, S K Turner, D Westaway, S Younkin, K H Ashe, G A Carlson, C Iadecola
Affiliations

Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation

K Niwa et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Figure 1
Figure 1
Relationship between Aβ1–40 (A) and Aβ1–42 (B) concentration and the increase in somatosensory CBF produced by whisker stimulation.
Figure 2
Figure 2
Effect of whisker stimulation on CBF (A) and CGU (B) in somatosensory pathways in APP+ (CBF, n = 5; CGU, n = 6) and APP− (CBF, n = 7; CGU, n = 6) mice (line Tg2123 M). *, P < 0.01 (t test) from contralateral; # P < 0.05 from APP−.
Figure 3
Figure 3
Effect of PS1mut overexpression in APP mice (2123F) on brain concentration of Aβ (A) and on the increase in CBF produced by whisker stimulation (B). (A) *, P < 0.01 from APP+/PS1mut−; n = 6/group. (B) *, P < 0.01 from APP−; # P < 0.01 from APP+ (analysis of variance); n = 6/group.
Figure 4
Figure 4
Effect of PS1mut overexpression on the correlation between brain Aβ concentration and attenuation of the increase in CBF produced by somatosensory activation. (A) The attenuation in CBF observed in APP+/PS1mut+ mice was plotted as a function of Aβ1–40 concentration. Notice that the points lie in or near the 95% confidence interval of the regression line obtained in APP mice (see Fig. 1A). (B) The attenuation in CBF observed in APP+/PS1mut+ mice was plotted as a function of Aβ1–42. Notice that the points fall outside the 95% confidence interval of the regression line obtained in APP mice (see Fig. 1B).
Figure 5
Figure 5
Effect of topical superfusion with Aβ peptides on resting CBF (A) and on the increase in CBF produced by vibrissal stimulation (B). *, P < 0.01 from Ringer, Aβ1–42, and Aβ40–1. P.U., perfusion units.
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