![]() ![]() It is difficult to explain the apparently conflicting results delivered from different animal models and different experimental methods. There was one study even showing that overall deletion of MyD88 in AD mice have no effects on neuroinflammation and Aβ deposition (Weitz, Gate, Rezai-Zadeh, & Town, 2014). Liu et al., 2014 Rangasamy et al., 2018), whereas, wild-type MyD88 was also reported to promote Aβ clearance and protect neurons (Michaud, Richard, & Rivest, 2011, 2012). For example, deletion of MyD88 or its downstream signaling molecule, IRAK4, and IKKβ, or disruption of the interaction between TLR2 and MyD88, attenuates Aβ pathology and neuronal death in APP-transgenic mice (Cameron et al., 2012 Hao et al., 2011 Lim et al., 2011 Y. However, results on the effects of innate immunity on Aβ pathology and neuronal degeneration in AD mice are often contradictory. Liu et al., 2014), or NLR family pyrin domain containing 3 (NLRP3) (Heneka et al., 2013) attenuates the degree of inflammation, shifts inflammatory activation from pro-inflammatory to anti-inflammatory profiles, or both in the brain of APP-transgenic mice. Liu et al., 2012), TLR4 (Song et al., 2011), myeloid differentiation factor 88 (MyD88) (Hao et al., 2011), interleukin receptor-associated kinase 4 (IRAK4) (Cameron et al., 2012), inhibitor of nuclear factor κ-B kinase subunit β (IKKβ) (Y. Deficiency of CD14 (Reed-Geaghan, Reed, Cramer, & Landreth, 2010), Toll-like receptor (TLR) 2 (S. Many studies through cross-breeding or bone marrow reconstruction have shown that the innate immune signaling regulates microglial activation in AD mice. However, activated microglia also exert a protective effect on neurons in AD mice by up-taking Aβ peptides (Michaud et al., 2013) and promoting degradation of phosphorylated tau proteins in neurons (Qin et al., 2016). Elimination of microglia at a late disease stage with noticeable Aβ already in the brain prevents the synaptic and neuronal loss in APP-transgenic mice (Spangenberg et al., 2016). In AD mouse models, which overexpress Alzheimer's amyloid precursor protein (APP) in neurons, microglia are activated and recruited to Aβ deposits (Bolmont et al., 2008 Meyer-Luehmann et al., 2008), and are more closely correlated with the impairment of cognitive performance than Aβ deposition (Focke et al., 2018). Genome-wide association studies correlated microglial genes (i.e., TREM2, APOE, CD33, ABCA7, and PLCG2) with the occurrence of late-onset AD, which highlights an essential role of microglia in AD pathogenesis (Lewcock et al., 2020). ![]() In summary, haploinsufficiency of MyD88 in microglia at a late disease stage attenuates pro-inflammatory activation and amyloid pathology, prevents the impairment of microvasculature and perhaps also protects LRP1-mediated Aβ clearance in the brain of APP/PS1-transgenic mice, all of which improves neuronal function of AD mice.Īlzheimer's disease (AD) is a progressive neurodegenerative disease pathologically characterized by extracellular amyloid β (Aβ) deposits, intracellular neurofibrillary tangles, and microglial activation (Heneka et al., 2015). Cell culture experiments further showed that treatments with interleukin-1β decreased LRP1 expression in pericytes. Moreover, MyD88-haploinsufficient microglia elevated protein levels of LRP1 in cerebral capillaries of APP/PS1-transgenic mice. Microglia with haploinsufficient expression of MyD88 also increased vasculature in the brain of APP/PS1-transgenic mice, which was associated with up-regulated transcription of osteopontin and insulin-like growth factor genes in microglia. To investigate mechanisms underlying the pathological improvement, we observed that haploinsufficiency of MyD88 increased microglial recruitment toward Aβ deposits, which might facilitate Aβ clearance. We observed that heterozygous deletion of myd88 gene in microglia decreased cerebral amyloid β (Aβ) load and improved cognitive function of AD mice, which was correlated with reduced number of microglia in the brain and inhibited transcription of inflammatory genes, for example, tnf-α and il-1β, in both brain tissues and individual microglia. Here, we conditionally deleted one allele of myd88 gene specifically in microglia in APP/PS1-transgenic mice by 6 months and analyzed AD-associated pathologies by 9 months. Growing evidence indicates that innate immune molecules regulate microglial activation in Alzheimer's disease (AD) however, their effects on amyloid pathology and neurodegeneration remain inconclusive.
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