Abstract
BackgroundAlzheimer’s disease (AD) is a neuropathology strongly associated with the activation of inflammatory pathways. Accordingly, inflammation resulting from obesity exacerbates learning and memory deficits in humans and in animal models of AD. Consequently, the long-term use of non-steroidal anti-inflammatory agents diminishes the risk for developing AD, but the side effects produced by these drugs limit their prophylactic use. Thus, plants natural products have become an excellent option for modern therapeutics. Malva parviflora is a plant well known for its anti-inflammatory properties.MethodsThe present study was aimed to determine the anti-inflammatory potential of M. parviflora leaf hydroalcoholic extract (MpHE) on AD pathology in lean and obese transgenic 5XFAD mice, a model of familial AD. The inflammatory response and Amyloid β (Aβ) plaque load in lean and obese 5XFAD mice untreated or treated with MpHE was evaluated by immunolocalization (Iba-1 and GFAP) and RT-qPCR (TNF) assays and thioflavin-S staining, respectively. Spatial learning memory was assessed by the Morris Water Maze behavioral test. Microglia phagocytosis capacity was analyzed in vivo and by ex vivo and in vitro assays, and its activation by morphological changes (phalloidin staining) and expression of CD86, Mgl1, and TREM-2 by RT-qPCR. The mechanism triggered by the MpHE was characterized in microglia primary cultures and ex vivo assays by immunoblot (PPAR-γ) and RT-qPCR (CD36) and in vivo by flow cytometry, using GW9662 (PPAR-γ inhibitor) and pioglitazone (PPAR-γ agonist). The presence of bioactive compounds in the MpHE was determined by HPLC.ResultsMpHE efficiently reduced astrogliosis, the presence of insoluble Aβ peptides in the hippocampus and spatial learning impairments, of both, lean, and obese 5XFAD mice. This was accompanied by microglial cells accumulation around Aβ plaques in the cortex and the hippocampus and decreased expression of M1 inflammatory markers. Consistent with the fact that the MpHE rescued microglia phagocytic capacity via a PPAR-γ/CD36-dependent mechanism, the MpHE possess oleanolic acid and scopoletin as active phytochemicals.ConclusionsM. parviflora suppresses neuroinflammation by inhibiting microglia pro-inflammatory M1 phenotype and promoting microglia phagocytosis. Therefore, M. parviflora phytochemicals represent an alternative to prevent cognitive impairment associated with a metabolic disorder as well as an effective prophylactic candidate for AD progression.
Highlights
Alzheimer’s disease (AD) is a neuropathology strongly associated with the activation of inflammatory pathways
M. parviflora hydroalcoholic extract improves glucose homeostasis in 5XFAD mice fed with a high fat diet Given that alteration in glucose homeostasis resulting from obesity exacerbates Amyloid β (Aβ)-induced memory loss [29] and that chronic inflammation is key for AD development [30], we evaluated whether long-term administration (8 months) of the M. parviflora leaf hydroalcoholic extract (MpHE) could attenuate the effects of an altered glucose metabolism on the development of the pathological changes associated with AD (Fig. 2a)
M. parviflora hydroalcoholic extract reduces amyloidosis and astrogliosis in the 5XFAD mice fed with a high fat diet To determine whether MpHA attenuates the negative effects of altered glucose metabolism resulting from obesity on memory loss induced by Aβ accumulation, first, we evaluated the accumulation of extracellular amyloid plaques in the hippocampus, a hallmark in the AD pathology (Fig. 3a)
Summary
Alzheimer’s disease (AD) is a neuropathology strongly associated with the activation of inflammatory pathways. Adjacent to the amyloid core, microglial cells are frequently found, whereas astrocytes usually surround the plaques Both cells types produce pro-inflammatory molecules like cytokines and oxygen-free radicals, among others [6]. The relevance of the inflammatory process in memory loss and neurodegeneration resulting from Aβ accumulation was recently shown in AD animal models lacking caspase-1 or other inflammasome components [8, 9]. Type II diabetes is a major risk factor for dementia and has been directly associated with the Aβ accumulation in the brain, due to deficient brain Aβ clearance resulting from the competition between insulin and the Aβ for binding to the insulin-degrading enzyme [13]. Chronic inflammatory process in the periphery might result in dementia
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