Cerebrovascular Dysfunction in Amyloid Precursor Protein Transgenic Mice: Contribution of Soluble and Insoluble Amyloid-β Peptide, Partial Restoration via γ-Secretase Inhibition

Abstract

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

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

“…We have shown similar CV deficits in young Tg2576 mice (13). Moreover, we provided the most direct evidence to date that endogenous soluble Aβ plays a causal role in these CV deficits when we found that depletion of soluble Aβ via γ-secretase inhibition restores CV function in young Tg2576 mice (13).…”

“…For example, Iadecola and coworkers have shown that young APP transgenic mice (Tg2576) exposed to elevated levels of Aβ 40 and Aβ 42 (but no CAA) have reduced baseline cerebral blood flow (CBF) and decreased CBF responses to topical vasodilators (23,24,26). We have shown similar CV deficits in young Tg2576 mice (13). Moreover, we provided the most direct evidence to date that endogenous soluble Aβ plays a causal role in these CV deficits when we found that depletion of soluble Aβ via γ-secretase inhibition restores CV function in young Tg2576 mice (13).…”

“…CAA is a well-recognized cause of intracerebral hemorrhage (7,8). It is also a major contributor to ischemic stroke and dementia (2, 9-12)-two conditions in which CAAinduced impairment in cerebral arteriole function is likely to play a fundamental role (13).…”

Ischemic brain injury in cerebral amyloid angiopathy

“…15,57,83,84 Support for this notion comes from experimental studies in mouse models of CAA, demonstrating decreased vascular reactivity in response to physiologic or pharmacologic stimuli compared with wild-type mice. 83,[85][86][87] Furthermore, mice with CAA showed increased susceptibility to induced ischemia, reflected by lower cerebral blood flow and increased infarct volume after middle cerebral artery occlusion. 83 It is not clear how well these animal models translate to the human disease, but the finding of impaired vascular reactivity in CAA is consistent with patient studies using functional transcranial Doppler 88 and functional MRI (fMRI).…”

Neurovascular function in Alzheimer's disease patients and experimental models

“…After this stage, both endotheliumdependent and -independent responses are impaired. Hence, Ab-directed therapy to deplete soluble Ab only partly restores function, suggesting irreversible CAA-induced damage (Han et al, 2008). However, the prevailing view of soluble Ab vasoactivity has been challenged by studies showing the absence of cerebrovascular deficits after Ab superfusion (Hu et al, 2008).…”