@misc{oai:repo.qst.go.jp:00070848,
 author = {Takuwa, Hiroyuki and Masamoto, Kazuto and Seki, Chie and Maruyama, Masahiro and Obata, Takayuki and Kawaguchi, Hiroshi and Kanno, Iwao and Higuchi, Makoto and Ito, Hiroshi and 田桑 弘之 and 正本 和人 and 関 千江 and 丸山 将浩 and 小畠 隆行 and 川口 拓之 and 菅野 巖 and 樋口 真人 and 伊藤 浩},
 month = {Aug},
 note = {Objectives: Cerebrovascular dysfunctions have been implicated in Alzheimer's disease 1. In order to explore mechanistic links between cerebrovascular dysfunctions and pathogenesis of Alzheimer's disease, we performed a repeated longitudinal evaluation of CBF response to whisker stimulation and accumulation of beta-amyloid in the somatosensory cortex of amyloid precursor protein (APP) transgenic and wild-type (WT) mice.
Methods: Long-term measurement of CBF response and behavior activity was performed2 every 2 to 4 weeks with laser-Doppler flowmetry (LDF) in awake APP transgenic mice aged from 3 to 27 months and WT mice aged from 3 to 37 months. Whisker stimulation was performed to provoke CBF response. On a separate date, amyloid and microvessels were fluorescently labeled with newly developed probe and sulforhodamine 101, respectively, and two-photon imaging (1024 by 1024 pixels) was performed with a z-step size of 4 micro;m (Fig. 1). Vascular and parenchymal amyloid deposits were evaluated separately. The thickness of vascular amyloid was measured at several points along a particular vessel as the difference between the outer diameter of the vessel wall and the outer diameter of the amyloid. Fraction of the vessels covered by amyloid was calculated as the ratio of the length of amyloid-positive sections along the vessel wall against the total vessel length. The parenchymal amyloid was evaluated by calculating the area covered by labeled amyloid in the parenchymal tissue.
Results: We observed that percentage increase of CBF during stimulation in APP transgenic mice declined with age from 3 months (21%) to 27 months (2%), while animal locomotion was preserved. In contrast, percentage increase of CBF in WT mice was relatively stable from 3 months (17%) to 37months (16%). There was a significant difference in the mean percentage increase of CBF between APP transgenic mice and WT mice aged 15 months or older (P < 0.01). In concurrence with this alteration, accumulation of amyloid became detectable in the parenchyma and vessel wall of small arteries at 14 months. Parenchymal amyloid gradually accumulated and the vascular amyloid expanded from the arteries to arterioles from 14 to 19 months. The thickness of the vascular amyloid at 19 months was greater by 60% than that at 14 months. The fraction of the vessels covered by amyloid at 14 months and 19 months were 62 % and 99 %, respectively. The size of parenchymal amyloid at 19 months increased by 70% relative to that at 14 months.
Discussion: The present results indicate that an age-dependent decline of cerebrovascular function was associated with accumulation of beta-amyloid in the brain. We hypothesized that cerebrovascular dysfunction in APP transgenic mice is caused by: i) neural dysfunctions due to parenchymal amyloid deposition; or ii) a mechanical restriction of cerebral vasodilatation by vascular amyloid. To elucidate this issue, it will be required to investigate CBF response to CO2 inhalation in APP transgenic mice showing attenuation of evoked CBF response to whisker stimulation.
Reference:
1. Iadecola C. (2004) Nat Rev Neurosci. 5(5):347-60.
2. Takuwa H, et al. (2011) Brain Res. 1369, 103-11., The 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM2012)},
 title = {Cerebrovascular dysfunction during somatosensory stimulation associated with beta-amyloid accumulation in APP transgenic mice.},
 year = {2012}
}