Intranasal losartan treatment decreased amyloid beta plaques 3.7-fold and reduced inflammatory markers in the APP/PS1 transgenic mouse model of Alzheimer Disease.
Does intranasal losartan reduce amyloid beta plaques and inflammation in the APP/PS1 transgenic mouse model of Alzheimer disease?
Intranasal losartan at sub-antihypertensive doses exerts neuroprotective and anti-inflammatory effects in a mouse model of Alzheimer's disease.
Effect estimate: 3.7-fold decrease
The local renin-angiotensin system (RAS) in the brain is a multitasking system controlling a plethora of essential functions such as neurogenic hypertension, baroreflexes, and sympathetic activity. Aside from its vasoactive actions, brain angiotensin II (AT-II) has also been implicated in the pathogenesis of cognitive decline, and beneficial effects of angiotensin receptor blockers (ARBs) in Alzheimer (AD) and Parkinson diseases (PD) are suggested. However, the use of ARBs at antihypertensive dosages would lead to unwanted hypotensive reactions in AD patients. Here we treated the APP/PS1 transgenic mouse model of AD with the ARB losartan (10 mg/kg body weight) to determine whether blockade of the AT-II receptor subtype 1 (AT1-R) with intranasal losartan, using at a dosage far below its systemic antihypertensive dose, could maintain its neuroprotective effects independent of its systemic vasoactive action. Intranasal losartan treatment (10 mg/kg every other day for 2 months) of APP/PS1 mice decreased amyloid beta (Abeta) plaques 3.7-fold. Blood serum levels of interleukin-12 (IL-12)p40/p70, IL-1beta, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in the vehicle-treated APP/PS1 mice. Intranasal losartan not only decreased IL-12p40/p70, IL-1beta, and GM-CSF, but also increased IL-10, which suppresses inflammation. Furthermore, losartan markedly increased tyrosine hydroxylase expression in the striatum and locus coeruleus. In conclusion, losartan exerts direct neuroprotective effects via its Abeta-reducing and antiinflammatory effects in the central nervous system (CNS). Therefore, intranasal losartan and potentially other ARBs, at concentrations below their threshold for altering systemic blood pressure, offer a new approach for the treatment of AD.
Danielyan et al. (Thu,) conducted a other in Alzheimer Disease (APP/PS1 transgenic mouse model). Intranasal losartan vs. vehicle was evaluated on Amyloid beta (Abeta) plaques (3.7-fold decrease). Intranasal losartan treatment decreased amyloid beta plaques 3.7-fold and reduced inflammatory markers in the APP/PS1 transgenic mouse model of Alzheimer Disease.