Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation - PubMed (original) (raw)
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. 2000.
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.
Figures
Figure 1
Relationship between Aβ1–40 (A) and Aβ1–42 (B) concentration and the increase in somatosensory CBF produced by whisker stimulation.
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
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
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. 1_A_). (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. 1_B_).
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.
Similar articles
- Abeta-induced vascular oxidative stress and attenuation of functional hyperemia in mouse somatosensory cortex.
Park L, Anrather J, Forster C, Kazama K, Carlson GA, Iadecola C. Park L, et al. J Cereb Blood Flow Metab. 2004 Mar;24(3):334-42. doi: 10.1097/01.WCB.0000105800.49957.1E. J Cereb Blood Flow Metab. 2004. PMID: 15091114 - FAD mutant PS-1 gene-targeted mice: increased A beta 42 and A beta deposition without APP overproduction.
Flood DG, Reaume AG, Dorfman KS, Lin YG, Lang DM, Trusko SP, Savage MJ, Annaert WG, De Strooper B, Siman R, Scott RW. Flood DG, et al. Neurobiol Aging. 2002 May-Jun;23(3):335-48. doi: 10.1016/s0197-4580(01)00330-x. Neurobiol Aging. 2002. PMID: 11959395 - NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide.
Park L, Anrather J, Zhou P, Frys K, Pitstick R, Younkin S, Carlson GA, Iadecola C. Park L, et al. J Neurosci. 2005 Feb 16;25(7):1769-77. doi: 10.1523/JNEUROSCI.5207-04.2005. J Neurosci. 2005. PMID: 15716413 Free PMC article. - Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta.
Park L, Wang G, Zhou P, Zhou J, Pitstick R, Previti ML, Younkin L, Younkin SG, Van Nostrand WE, Cho S, Anrather J, Carlson GA, Iadecola C. Park L, et al. Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5063-8. doi: 10.1073/pnas.1015413108. Epub 2011 Mar 7. Proc Natl Acad Sci U S A. 2011. PMID: 21383152 Free PMC article. - Alzheimer's disease.
De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV. De-Paula VJ, et al. Subcell Biochem. 2012;65:329-52. doi: 10.1007/978-94-007-5416-4_14. Subcell Biochem. 2012. PMID: 23225010 Review.
Cited by
- Cerebrovascular Dysfunction in Alzheimer's Disease and Transgenic Rodent Models.
Fang X, Fan F, Border JJ, Roman RJ. Fang X, et al. J Exp Neurol. 2024;5(2):42-64. doi: 10.33696/neurol.5.087. J Exp Neurol. 2024. PMID: 38434588 Free PMC article. - In conversation with Costantino Iadecola.
Floriddia E. Floriddia E. Nat Neurosci. 2023 Dec;26(12):2042-2045. doi: 10.1038/s41593-023-01505-2. Nat Neurosci. 2023. PMID: 37973870 No abstract available. - Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress.
Uekawa K, Hattori Y, Ahn SJ, Seo J, Casey N, Anfray A, Zhou P, Luo W, Anrather J, Park L, Iadecola C. Uekawa K, et al. Mol Neurodegener. 2023 Oct 3;18(1):73. doi: 10.1186/s13024-023-00660-1. Mol Neurodegener. 2023. PMID: 37789345 Free PMC article. - Post-Ischemic Permeability of the Blood-Brain Barrier to Amyloid and Platelets as a Factor in the Maturation of Alzheimer's Disease-Type Brain Neurodegeneration.
Pluta R, Miziak B, Czuczwar SJ. Pluta R, et al. Int J Mol Sci. 2023 Jun 27;24(13):10739. doi: 10.3390/ijms241310739. Int J Mol Sci. 2023. PMID: 37445917 Free PMC article. Review.
References
- Mattson M P. Physiol Rev. 1997;77:1081–1132. - PubMed
- Selkoe D J. Nature (London) 1999;399:A23–A31. - PubMed
- Levy-Lahad E, Bird T D. Ann Neurol. 1996;40:829–840. - PubMed
- Dickson D W. J Neuropathol Exp Neurol. 1997;56:321–339. - PubMed
- Vinters H V, Wang Z Z, Secor D L. Brain Pathol. 1996;6:179–195. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- R01 NS037853/NS/NINDS NIH HHS/United States
- R01 NS033249/NS/NINDS NIH HHS/United States
- NS37853/NS/NINDS NIH HHS/United States
- NS38252/NS/NINDS NIH HHS/United States
- NS33249/NS/NINDS NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources