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

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

doi:10.3390/ph14020166

Cited by 20 publications

(14 citation statements)

References 52 publications

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“…Another possible mechanism behind the reduction of Aβ pathology by DTMB is the regulation of Aβ degrading enzyme. Previously, it has been reported that selective PPARγ agonist like losartan can decrease Aβ pathology by enhancing the Aβ degrading enzymes, like neprilysin and insulin-degrading enzyme (IDE) [41,42]. Since DTMB also acts as a partial PPARγ agonist, we checked the differentially expressed genes through RNAseq experiment to confirm whether Aβ pathology is reduced by downregulation of amyloid beta degrading enzymes (Supplementary data 6).…”

Section: Discussionmentioning

confidence: 99%

Synthetic PPAR Agonist DTMB Alleviates Alzheimer's Disease Pathology by Inhibition of Chronic Microglial Inflammation in 5xFAD Mice

Kang

et al. 2022

Neurotherapeutics

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Abnormal productions of amyloid beta (Aβ) plaque and chronic neuroinflammation are commonly observed in the brain of patients with Alzheimer’s disease, and both of which induce neuronal cell death, loss of memory, and cognitive dysfunction. However, many of the drugs targeting the production of Aβ peptides have been unsuccessful in treating Alzheimer’s disease. In this study, we identified synthetic novel peroxisome proliferator-activating receptor (PPAR) agonist, DTMB, which can ameliorate the chronic inflammation and Aβ pathological progression of Alzheimer’s disease. We discovered that DTMB attenuated the proinflammatory cytokine production of microglia by reducing the protein level of NF-κB. DTMB also improved the learning and memory defects and reduced the amount of Aβ plaque in the brain of 5xFAD mice. This reduction in Aβ pathology was attributed to the changes in gliosis and chronic inflammation level. Additionally, bulk RNA-sequencing showed that genes related to inflammation and cognitive function were changed in the hippocampus and cortex of DTMB-treated mice. Our findings demonstrate that DTMB has the potential to be a novel therapeutic agent for Alzheimer’s disease. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Synthetic PPAR Agonist DTMB Alleviates Alzheimer's Disease Pathology by Inhibition of Chronic Microglial Inflammation in 5xFAD Mice

Kang

et al. 2022

Neurotherapeutics

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“…Following this line of thought, drugs acting on cardiovascular and cerebrovascular dysfunctions, BBB and neurovascular unit, hypertension, atherosclerosis, amyloid cerebral angiopathy and lymphatic/glyphic system dysfunction could be useful for AD treatment. For instance, losartan, an antihypertensive drug, reduced plasma and brain Aβ1-42 levels in a murine model of AD [126,127]. In this sense, different antihypertensive drugs that could be used against neurodegeneration are currently under study, including ARAII drugs (candesartan, telmisartan) and combination treatments such as telmisartan + perindopril (ARAII + ACE inhibitors), and losartan + amlodipine + atorvastatin + exercise (ARAII + Ca 2+ blocker + an anti-cholesterol agent) (NCT02913664) [33,[128][129][130].…”

Section: Cardiovascular Risk Factors As Therapeutic Targetsmentioning

confidence: 99%

Impact of New Drugs for Therapeutic Intervention in Alzheimer’s Disease

Olloquequi¹,

Ettcheto²,

Cano³

et al. 2022

Front. Biosci. (Landmark Ed)

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The increases in population ageing and growth are leading to a boosting in the number of people living with dementia, Alzheimer's disease (AD) being the most common cause. In spite of decades of intensive research, no cure for AD has been found yet. However, some treatments that may change disease progression and help control symptoms have been proposed. Beyond the classical hypotheses of AD etiopathogenesis, i.e., amyloid beta peptide (Aβ) accumulation and tau hyperphosphorylation, a trend in attributing a key role to other molecular mechanisms is prompting the study of different therapeutic targets. Hence, drugs designed to modulate inflammation, insulin resistance, synapses, neurogenesis, cardiovascular factors and dysbiosis are shaping a new horizon in AD treatment. Within this frame, an increase in the number of candidate drugs for disease modification treatments is expected, as well as a focus on potential combinatory multidrug strategies.The present review summarizes the latest advances in drugs targeting Aβ and tau as major contributors to AD pathophysiology. In addition, it introduces the most important drugs in clinical studies targeting alternative mechanisms thought to be involved in AD's neurodegenerative process.

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“…There is growing evidence that RAS can be effectively targeted to reduce neuroinflammation in several brain pathologies, namely, Alzheimer (81)(82)(83)(84)(85)(86), Parkinson (87)(88)(89), ischemic stroke (90,91), traumatic brain injury (TBI) (92,93), hypertension (94,95) and inflammation (96) (Figure 2). Reduced astro-and micro-gliosis has been reported after blockade of the ACE/Ang-II/AT 1 R pathway, leading to a reduction in cytokine production and a better functional outcome (81,83,86,90,93,96,97).…”

Section: Ras and Neuroinflammationmentioning

confidence: 99%

Angiotensin-(1–7) as a Potential Therapeutic Strategy for Delayed Cerebral Ischemia in Subarachnoid Hemorrhage

et al. 2022

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Aneurysmal subarachnoid hemorrhage (SAH) is a substantial cause of mortality and morbidity worldwide. Moreover, survivors after the initial bleeding are often subject to secondary brain injuries and delayed cerebral ischemia, further increasing the risk of a poor outcome. In recent years, the renin–angiotensin system (RAS) has been proposed as a target pathway for therapeutic interventions after brain injury. The RAS is a complex system of biochemical reactions critical for several systemic functions, namely, inflammation, vascular tone, endothelial activation, water balance, fibrosis, and apoptosis. The RAS system is classically divided into a pro-inflammatory axis, mediated by angiotensin (Ang)-II and its specific receptor AT1R, and a counterbalancing system, presented in humans as Ang-(1–7) and its receptor, MasR. Experimental data suggest that upregulation of the Ang-(1–7)/MasR axis might be neuroprotective in numerous pathological conditions, namely, ischemic stroke, cognitive disorders, Parkinson’s disease, and depression. In the presence of SAH, Ang-(1–7)/MasR neuroprotective and modulating properties could help reduce brain damage by acting on neuroinflammation, and through direct vascular and anti-thrombotic effects. Here we review the role of RAS in brain ischemia, with specific focus on SAH and the therapeutic potential of Ang-(1–7).

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

Cited by 20 publications

References 52 publications

Synthetic PPAR Agonist DTMB Alleviates Alzheimer's Disease Pathology by Inhibition of Chronic Microglial Inflammation in 5xFAD Mice

Synthetic PPAR Agonist DTMB Alleviates Alzheimer's Disease Pathology by Inhibition of Chronic Microglial Inflammation in 5xFAD Mice

Impact of New Drugs for Therapeutic Intervention in Alzheimer’s Disease

Angiotensin-(1–7) as a Potential Therapeutic Strategy for Delayed Cerebral Ischemia in Subarachnoid Hemorrhage

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