Losartan Improves Memory, Neurogenesis and Cell Motility in Transgenic Alzheimer's Mice.

Henning Johannes Drews,Elke Schaeffeler,Marine Buadze,Thomas Lang,Christoph H Gleiter,Ali Lourhmati,Lusine Danielyan,Roman Klein,William H Frey Ii,Matthias Schwab,Tom C.G.M De Vries,Leah R Hanson,Inge A.E.W Thijssen-Van Loosdregt,Torgom Seferyan

doi:10.3390/ph14020166

Abstract

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment.

Highlights

Introduction distributed under the terms andThe local renin-angiotensin system (RAS) in the CNS has been proposed to play a critical role in the pathological hallmarks of Alzheimer’s disease (AD), such as memory deficits, neuroinflammation and impaired neurogenesis
To prove that the observed effects of losartan on the memory, protein and gene expression are independent of its blood pressure (BP)-lowering feature, we measured BP at the beginning and during the period of losartan administration
Our data show that losartan modulates the factors duced neuroinflammation; (5) enhanced Glu- and Aβ-clearance and (6) the improvement interconnecting some of the aforementioned processes, well as theour proliferation andthat migrational capacity of factorsby interconnecting some of the aforementioned processes, as well as the proliferation and migrational capacity of astrocytes affected by Aβ

Summary

Introduction

Introduction distributed under the terms andThe local renin-angiotensin system (RAS) in the CNS has been proposed to play a critical role in the pathological hallmarks of Alzheimer’s disease (AD), such as memory deficits, neuroinflammation and impaired neurogenesis. Pharmaceuticals 2021, 14, 166 and neuroinflammation (for review see [1,2]), the AT1R blockers (ARBs) were shown to blunt these effects when administered systemically or intranasally in rodent models of AD [3,4,5,6]. Despite the uniform confirmation of AT1R blockade (ARB)-mediated memory improvement and anti-inflammatory effects in AD models, the impact of this drug class on amyloid (Aβ) plaque pathology remains controversial. Since memory improvement has been previously shown in transgenic AD mice following treatment with telmisartan [4], the potential effect of losartan on memory deficits in APP/PS1 mice reported here would support the notion of a class-wide effect of sartans on cognitive performance in transgenic mouse models of AD

Methods

Results

Conclusion