24 Aug 2002

The beta-amyloid that accumulates in cerebral blood vessels of AβPP-transgenic mice ultimately affects cerebral blood flow in these animals, according to a study in the current issue of the Journal of Neuroscience.

The AbPP23-transgenic mice, which over-expresses human amyloid precursor protein with the Swedish double mutation (KM670/671NL), accumulate Aβ in cerebral blood vessels despite the fact that they express the human disease transgene only in neurons (Calhoun, 1999). This accumulation is accompanied by cerebrovascular pathologies that mimic those seen in older humans and Alzheimer's patients, such as a loss of vascular smooth muscle cells, aneurysm-like vasodilations, and other blood vessel abnormalities (Winkler, 2001).

In the current report, Markus Rudin, Thomas Mueggler, and colleagues at Novartis Pharma in Basel, Switzerland, set out to determine if these pathologies changed the ability of cerebral blood vessels to regulate blood flow, and if functional MRI could be used to study any such changes. When they challenged the mice biochemically with the GABA[A]-antagonist bicuculline, wild-type mice showed the expected transient increase in cerebral blood volume (CBV) at 7, 15 and 23 months. Their AβPP23 littermates, on the other hand, exhibited a significantly reduced CBV increase when tested at 23 months. The authors speculate that this could reflect impaired neuronal excitability, perhaps related to Aβ-mediated damage to cholinergic systems.

The reduced CBV response might also reflect decreased vascular reactivity, something the researchers then assayed with the carbonic anhydrase inhibitor acetazolamide. Normally, acetazolamide transiently increases cerebral blood flow (by a still-unexplained mechanism). Again, aged AβPP23 mice showed a significantly weaker response than wild-type littermates.

The researchers conclude that fMRI is a useful method to explore the effects of cerebral amyloid angiopathy in AβPP23 mice. Such experiments might, in turn, help elucidate the changes in blood flow and brain activation seen in MRI experiments with patients with early and later stages of Alzheimer's.—Hakon Heimer