Abstract 748: Certain Anti-hypertensive Agents Reduce β-Amyloid Neuropathology and Improve Cognition in a Mouse Model of Alzheimer’s Disease.
Recent studies suggest that certain cardiovascular antihypertensive agents decrease Alzheimer’s disease (AD) incidence (Forette et al., 2002; Lopez-Arrieta and Birke, 2002; Guo et al, 1999). However, other investigations failed to support these findings (In’t Veld et al, 2001). We hypothesize that this apparent inconsistency may be related to the differences between antihypertensive drugs as AD disease-modifying agents. Brain β-amyloid (Aβ) neuropathology is a major hallmark of AD. We tested the possibility that certain antihypertensive agents may affect AD progression by influencing formation of Aβ peptides within the brain. In a high-throughput screening of 150 cardiovascular drugs, we identified 24 agents capable of significantly lowering Aβ activity in primary neuron cell cultures derived from embryonic Tg2576 mice used to model AD. Twenty-one of the 24 agents were anti-hypertensives. In in-vivo studies, one of these drugs, valsartan, significantly reduced the content of Aβ peptides in the cortex and hippocampus of Tg2576 AD mice by 50% and 56% respectively (p < 0.05 compared to age- and gender-matched non-treated control Tg2576 mice). Also, valsartan treatment attenuated the deterioration of spatial memory in these mice, assessed by a Morris circular water maze paradigm (ANOVA: p < 0.00288 vs. control Tg2576 mice). These studies suggest that certain antihypertensive agents may prevent the development and/or progression of Alzheimer’s dementia through the inhibition of Aβ in the brain.