27 October 2007. Researchers once hotly debated whether non-steroidal anti-inflammatories (NSAIDs) reduce pathology in Alzheimer disease. The argument was partly resolved when it was discovered that certain NSAIDs have more than anti-inflammatory activity. Some of them, including ibuprofen, reduce the amount of Aβ42 produced by γ-secretase (see ARF related news story). Could a similar unexpected side effect resolve the debate over the protective effects of anti-hypertension medication? Perhaps. In the November Journal of Clinical Investigation, researchers led by Giulio Pasinetti at Mount Sinai School of Medicine, New York, report that some anti-hypertensives have anti-Aβ activity in vitro, and that one in particular, valsartan, improves spatial learning and reduces Aβ pathology in mice. The findings may not only help explain some previous findings, but might lead to a new rationale for treatment.
If simply lowering blood pressure reduced the risk of Alzheimer disease, then the millions of patients taking one of the currently prescribed anti-hypertensives would be protected. However, the data on hypertensives is equivocal, and interpretation is complicated by the existence of 55 currently approved medicines in eight different classes, including β-adrenergic blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockers (ARB), and diuretics (see ARF related news story). In an attempt to clarify the observational data, Pasinetti and colleagues decided to test anti-hypertension drugs to determine if any of them modulate Aβ pathology.
First author Jun Wang and colleagues began by testing all 55 drugs in an in-vitro screen, adding the drugs to primary neuronal cultures from Tg2576 transgenic mice. They found that seven of the drugs, representing six different classes, reduced Aβ accumulation in the conditioned medium. Because there is now overwhelming evidence that oligomers of Aβ are the most toxic species, Wang then tested these seven, including valsartan and another ARB, losartan, to see if they could prevent Aβ oligomerization in vitro (see Klein et al., 2002). The researchers found that valsartan completely prevented the formation of high molecular weight (HMW) species, while losartan had less of an effect. None of the other five drugs affected oligomerization in this assay.
Given the in vitro effects, Wang and colleagues decided to test if valsartan can protect Tg2576 mice against Aβ pathology. Valsartan dosing in humans equates to about 20-60 mg/Kg/day in the mouse, so the authors treated the animals daily with 10 and 40 mg/Kg for 5 months. They began dosing at 6 months old, just before amyloid plaques begin to accumulate. The researchers found that although the chronic treatment had no effect on blood pressure (systolic, diastolic, or mean) the animals performed significantly better than Tg2576 controls in a water maze test of spatial learning and memory. The researchers also found that the ARB reduced the amount of high molecular weight Aβ species in the brain by two- to threefold.
Given the effects of valsartan on Aβ oligomerization, it might be safe to assume that is how the drug led to the improved learning and memory. But the researchers also found that the drug also lowered the amount of soluble Aβ in the brains of treated mice by about twofold. Could the drug also modulate γ-secretase, just like some NSAIDs?
That seems not to be the case. The researchers did not find any effect on α-, β-, or γ-secretase activity in the brain. In addition, levels of α-, β-, or γ-carboxyterminal fragments and the soluble fragments, sAPPα and sAPPβ, were unchanged by the treatment. The data would thus seem to exclude an effect on APP processing, which made the authors focus on clearance. They found a slight, though not statistically significant, reduction in serum Aβ after valsartan treatment. This could perhaps explain the lower soluble Aβ in the brain because lowering Aβ in the periphery could create a sink effect, pulling more of the peptide out of the CNS. More importantly, perhaps, they found a significant increase in the activity of membrane-bound insulin-degrading enzyme (IDE) in the cerebral cortex, which is thought to play a major role in Aβ degradation. They found no change in activity of neprilysin or endothelin-converting enzyme 1, two other possible Aβ degradation enzymes.
“Collectively, our evidence suggests that valsartan treatment might prevent Aβ-related spatial memory reference deficits in the Tg2576 AD mouse model through a combination of multiple mechanisms: (a) reducing Aβ aggregation into HMW Aβ species; (b) increasing Aβ degradation by IDE; and possibly (c) promoting sinking of Aβ peptides from the brain to the periphery,” write the authors.
How valsartan prevents oligomerization or leads to increased IDE activity is not clear. Nonetheless, the authors suggest that these findings might “provide the appropriate impetus for clinical trials in vulnerable human patients,” such as those with mild cognitive impairment. But they caution that there is no data as yet to support the idea that valsartan has any impact on the incidence or progression of cognitive impairments.—Tom Fagan.
Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I, Bartholomew S, Rosendorff C, Pasinetti GM. Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J. Clin. Invest. 2007 November. Abstract