We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid β (Aβ) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes at 9 wk of age in male mice only. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes. Transcriptomic studies revealed significant differences between vehicle versus ABX-treated male mice and FMT from Tg mice into ABX-treated mice largely restored the transcriptome profiles to that of the Tg donor animals. Finally, colony-stimulating factor 1 receptor (CSF1R) inhibitor-mediated depletion of microglia in ABX-treated male mice failed to reduce cerebral Aβ amyloidosis. Thus, microglia play a critical role in driving gut microbiome–mediated alterations of cerebral Aβ deposition.

Alzheimer's disease (AD) is a neurodegenerative disorder and the primary cause of age‐related dementia. The etiology of AD is complex and has not been completely elucidated. Herein, we report that treatment with elastin‐like polypeptides (ELPs), a component of the brain extracellular matrix (ECM), significantly increased the levels of AD‐related amyloid‐β peptides (Aβ) both in vitro and in vivo. Regarding the molecular mechanism(s), the upregulation of Aβ levels was related to increased proteolytic processing of the amyloid precursor protein. Furthermore, nesting tests demonstrated that the ELP‐treated animals showed significant neurobehavioral deficits with cognitive impairment. These results suggest that the elastin is associated with AD‐related pathological and behavioral changes. This finding presents a new aspect for Alzheimer's amyloidosis event and provides a great promise in developing ELP‐based model systems to better understand the pathogenesis of AD.

Necrostatin-1 is an inhibitor of necroptosis, a form of programmed cell death that has been reported to be involved in various neurological diseases. Presently, the role of necroptosis in neuropathic pain induced by peripheral nerve injury is still unclear. This study was focused on investigating the potential effects of necroptosis in the development and progression of neuropathic pain in a rat model and the possible neuroprotective effects of necrostatin-1 in neuropathic pain. The results indicated that the necroptosis-related proteins RIP1 and RIP3 significantly increased postoperation in the spinal cord in a neuropathic pain model and peaked 7 days postoperation, which was consistent with the time-dependent changes of hyperalgesia. Additionally, we found that peripheral nerve injury-related behavioral and biochemical changes were significantly reduced by necrostatin-1. In particular, hyperalgesia was attenuated, and the levels of RIP1 and RIP3 were decreased. Furthermore, the ultrastructure of necrotic cell death and neuroinflammation were alleviated by necrostatin-1. Collectively, these results suggest that necroptosis is an important mechanism of cell death in neuropathic pain induced by peripheral nerve injury and that necrostatin-1 may be a promising neuroprotective treatment for neuropathic pain.

The amyloid cascade hypothesis of Alzheimer's disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to formation of β-amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of β-amyloid protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of β-amyloid plaques in relationship to APP expression in astrocytes and cellular consequences are largely unknown. Here, we aimed to investigate astrocyte-related pathologic changes of βamyloid and APP using immunohistochemistry and biochemical studies in both animal and cell models. We utilized 5XFAD transgenic mice and found age-dependent upregulation of APP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that APP proteins presented well-defined punctate immunoreactivity in young animals that in contrast showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ 42 resulted in down-stream astrocyte autonomous changes, including upregulation in APP and BACE1 levels, as well as prolonged amyloidogenesis that can be reduced by pharmacological inhibition of BACE1. Collectively, our results showed that age-dependent APP up-regulation in astrocytes is a key feature in AD, which will not only provide novel insights for understanding AD progression, but also may offer new therapeutic strategies for treating AD.

suggest this revelation of the diverse functions of ELPs and other ECM may pave the way to uncover new specific microglia-targeted approaches related to AD and potentially other neurological disorders.

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The Fc gamma receptor I (FcγRI; CD64) is the high-affinity receptor of the immunoglobulin G protein (IgG). It is usually expressed in immune cells and has recently been identified to distribute in the nervous system and play critical roles in various neurological disorders. Presently, the impacts of FcγRI in neuropathic pain was largely unknown. Here, we aimed to investigate the impacts of FcγRI in neuropathic pain through pain-related neurobehavioral studies and underlying mechanisms by biochemical methods in animal and cell models. Specifically, we first utilized the chronic constriction injury (CCI) rat model that displayed neuropathic pain related symptoms and signs, including thermal hyperalgesia and mechanical allodynia. These neurobehavioral defects were significantly attenuated by the anti-FcγRI antibody, which was associated with reduced levels of neuropeptide substance P, C3, and TNF-α. Furthermore, we validated our animal findings using the embryonically neural crest-originated PC12 cell model. We found that stimulation of the IgG immune complex led to increased levels of FcγRI and inflammatory mediators, which were attenuated by the anti-FcγRI antibody in these cells. Collectively, our results from animal and cell-based studies suggest that FcγRI is a critical player for peripheral nerve injury-induced neuropathic pain by mediating pain-related immunological events, which therefore may provide a new therapeutic target for protection against chronic pain.