Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gamma-secretase inhibition

J Neurosci. 2008 Dec 10;28(50):13542-50. doi: 10.1523/JNEUROSCI.4686-08.2008.


The contributing effect of cerebrovascular pathology in Alzheimer's disease (AD) has become increasingly appreciated. Recent evidence suggests that amyloid-beta peptide (Abeta), 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 Abeta but no cerebral amyloid angiopathy (CAA). These studies suggest but do not prove that soluble Abeta 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 Abeta 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 Abeta improved vessel function in young and to a lesser degree older Tg2576 mice. These results strongly suggest that both soluble and insoluble Abeta cause cerebrovascular dysfunction, that mechanisms other than Abeta-induced alteration in vessel integrity are responsible, and that anti-Abeta therapy may have beneficial vascular effects in addition to positive effects on parenchymal amyloid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / physiopathology
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Brain / blood supply*
  • Brain / pathology
  • Cerebral Amyloid Angiopathy / metabolism
  • Cerebral Amyloid Angiopathy / pathology
  • Cerebral Amyloid Angiopathy / physiopathology
  • Cerebrovascular Circulation / physiology*
  • Mice
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / physiopathology*


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Amyloid Precursor Protein Secretases