Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: Contribution of soluble and insoluble amyloid-β peptide, partial restoration via γ-secretase inhibition

Byung Hee Han, Meng Liang Zhou, Fadi Abousaleh, Robert P. Brendza, Hans H. Dietrich, Jessica Koenigsknecht-Talboo, John R. Cirrito, Eric Milner, David M. Holtzman, Gregory J. Zipfel

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109 Scopus citations

Abstract

The contributing effect of cerebrovascular pathology in Alzheimer's disease (AD) has become increasingly appreciated. Recent evidence suggests that amyloid-β peptide (Aβ), the same peptide found in neuritic plaques of AD, may play a role via its vasoactive properties. Several studies have examined young Tg2576 mice expressing mutant amyloid precursor protein (APP) and having elevated levels of soluble Aβ but no cerebral amyloid angiopathy (CAA). These studies suggest but do not prove that soluble Aβ can significantly impair the cerebral circulation. Other studies examining older Tg2576 mice having extensive CAA found even greater cerebrovascular dysfunction, suggesting that CAA is likely to further impair vascular function. Herein, we examined vasodilatory responses in young and older Tg2576 mice to further assess the roles of soluble and insoluble Aβ on vessel function. We found that (1) vascular impairment was present in both young and older Tg2576 mice; (2) a strong correlation between CAA severity and vessel reactivity exists; (3) a surprisingly small amount of CAA led to marked reduction or complete loss of vessel function; 4) CAA-induced vasomotor impairment resulted from dysfunction rather than loss or disruption of vascular smooth muscle cells; and 5) acute depletion of Aβ improved vessel function in young and to a lesser degree older Tg2576 mice. These results strongly suggest that both soluble and insoluble Aβ cause cerebrovascular dysfunction, that mechanisms other than Aβ-induced alteration in vessel integrity are responsible, and that anti-Aβ therapy may have beneficial vascular effects in addition to positive effects on parenchymal amyloid.

Original languageEnglish
Pages (from-to)13542-13550
Number of pages9
JournalJournal of Neuroscience
Volume28
Issue number50
DOIs
StatePublished - Dec 10 2008

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • Cerebral amyloid angiopathy
  • Hypercapnia
  • Vascular function
  • γ-secretase

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