The Alzheimer's disease-associated gene TREML2 modulates inflammation by regulating microglia polarization and NLRP3 inflammasome activation

Triggering receptor expressed on myeloid cells-like 2(TREML2)is a newly identified susceptibility gene for Alzheimer's disease(AD).It encodes a microglial inflammation-associated receptor.To date,the potential role of mic roglial TREML2 in neuroinflammation in the context of AD remains unclear.In this study,APP/PS1 mice were used to investigate the dynamic changes of TREML2 levels in brain during AD progression.In addition,lipopolysaccharide(LPS)stimulation of primary microglia as well as a lentivirus-mediated TREML2 overexpression and knockdown were employed to explore the role of TREML2 in neuroinflammation in the context of AD.Our res ults show that TREML2 levels gradually increased in the brains of AP P/PS1 mice during disease progression.LPS stimulation of primary microglia led to the release of inflammato ry cytokines including interleukin-1β,inte rleukin-6,and tumor necrosis factor-a in the culture medium.The LPS-induced mic roglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knoc kdown.LPS increased the levels of mic roglial M1-type polarization marker inducible nitric oxide synthase.This effect was enhanced by TREML2 overexpression and ameliorated by TREML2 knockdown.Furthermore,the levels of microglial M2-type polarization markers CD206 and ARG1 in the primary microglia were reduced by TREML2 overexpression and elevated by TREML2 knockdown.LPS stimulation increased the levels of NLRP3 in primary microglia.The LPS-induced increase in NLRP3 was further elevated by TREML2 overexpression and alleviated by TREML2 knockdown.In summary,this study provides the first evidence that TREML2 modulates inflammation by regulating microglial polarization and NLRP3 inflammasome activation.These findings reveal the mechanisms by which TREML2 regulates microglial inflammation and suggest that TREML2 inhibition may represent a novel therapeutic strategy for AD.

Lamotrigine protects against cognitive deficits,synapse and nerve cell damage,and hallmark neuropathologies in a mouse model of Alzheimer’s disease

Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.

Angiotensin-(1–7)reducesα-synuclein aggregation by enhancing autophagic activity in Parkinson's disease

Abnormal accumulation ofα-synuclein contributes to the formation of Lewy bodies in the substantia nigra,which is considered the typical pathological hallmark of Parkinson's disease.Recent research indicates that angiotensin-(1-7)plays a crucial role in several neurodegenerative disorders,including Parkinson's disease,but the underlying mechanisms remain elusive.In this study,we used intraperitoneal administration of rotenone to male Sprague-Dawley rats for 4 weeks to establish a Parkinson's disease model.We investigated whether angiotensin-(1-7)is neuroprotective in this model by continuous administration of angiotensin-(1-7)into the right substantia nigra for 4 weeks.We found that angiotensin-(1-7)infusion relieved characteristic parkinsonian behaviors and reducedα-synuclein aggregation in the substantia nigra.Primary dopaminergic neurons were extracted from newborn Sprague-Dawley rat substantia nigras and treated with rotenone,angiotensin-(1-7),and/or the Mas receptor blocker A-779 for 24 hours.After binding to the Mas receptor,angiotensin-(1-7)attenuated apoptosis andα-synuclein aggregation in rotenone-treated cells.Primary dopaminergic neurons were also treated with angiotensin-(1-7)and/or the autophagy inhibitor 3-methyladenine for 24 hours.Angiotensin-(1-7)increasedα-synuclein removal and increased the autophagy of rotenone-treated cells.We conclude that angiotensin-(1-7)reducesα-synuclein aggregation by alleviating autophagy dysfunction in Parkinson's disease.Therefore,the angiotensin-(1-7)/Mas receptor axis plays an important role in the pathogenesis of Parkinson's disease and angiotensin-(1-7)has potential therapeutic value for Parkinson's disease.All experiments were approved by the Biological Research Ethics Committee of Nanjing First Hospital(approval No.DWSY-2000932)in January 2020.

Indirubin-3′-monoxime suppresses amyloid-beta-induced apoptosis by inhibiting tau hyperphosphorylation

Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apoptosis in Alzheimer's disease. Here, we found that indirubin-3′-monoxime improved the morphology and increased the survival rate of SHSY5 Y cells exposed to amyloid-beta 25–35(Aβ25–35), and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3′-monoxime inhibited phosphorylation of glycogen synthase kinase-3β(GSK-3β). Our results suggest that indirubin-3′-monoxime reduced Aβ25–35-induced apoptosis by suppressing tau hyperphosphorylation via a GSK-3β-mediated mechanism. Indirubin-3′-monoxime is a promising drug candidate for Alzheimer's disease.