Vascular Dysfunction in a Transgenic Model of Alzheimer's Disease: Effects of CB1R and CB2R Cannabinoid Agonists

There is evidence of altered vascular function, including cerebrovascular, in Alzheimer's disease (AD) and transgenic models of the disease. Indeed vasoconstrictor responses are increased, while vasodilation is reduced in both conditions. beta-Amyloid (A beta) appears to be responsible, at least in part, of alterations in vascular function. Cannabinoids, neuroprotective and anti-inflammatory agents, induce vasodilation both in vivo and in vitro. We have demonstrated a beneficial effect of cannabinoids in models of AD by preventing glial activation. In this work we have studied the effects of these compounds on vessel density in amyloid precursor protein (APP) transgenic mice, line 2576, and on altered vascular responses in aortae isolated ring. First we showed increased collagen IV positive vessels in AD brain compared to control subjects, with a similar increase in TgAPP mice, which was normalized by prolonged oral treatment with the CB1/CB2 mixed agonist WIN 55,212-2 (WIN) and the CB2 selective agonist JWH-133 (JWH). In Tg APP mice the vasoconstriction induced by phenylephrine and the thromboxane agonist U46619 was significantly increased, and no change in the vasodilation to acetylcholine (ACh) was observed. Tg APP displayed decreased vasodilation to both cannabinoid agonists, which were able to prevent decreased ACh relaxation in the presence of A beta. In summary, we have confirmed and extended the existence of altered vascular responses in Tg APP mice. Moreover, our results suggest that treatment with cannabinoids may ameliorate the vascular responses in AD-type pathology.