Alzheimer's disease (AD) is the most common type of dementia. Almost two-thirds of patients with AD are female. The reason for the higher susceptibility to AD onset in women is unclear. However, hormone changes during the menopausal transition are known to be associated with AD. Most recently, we reported that follicle-stimulating hormone (FSH) promotes AD pathology and enhances cognitive dysfunctions via activating the CCAAT-enhancer-binding protein (C/EBPβ)/asparagine endopeptidase (AEP) pathway. This review summarizes our current understanding of the crucial role of the C/EBPβ/AEP pathway in driving AD pathogenesis by cleaving multiple critical AD players, including APP and Tau, explaining the roles and the mechanisms of FSH in increasing the susceptibility to AD in postmenopausal females. The FSH-C/EBPβ/AEP pathway may serve as a novel therapeutic target for the treatment of AD.
Female ; Humans ; Male ; Alzheimer Disease/pathology* ; CCAAT-Enhancer-Binding Protein-beta/metabolism* ; Cognitive Dysfunction/metabolism* ; Signal Transduction ; Follicle Stimulating Hormone

The netrins and their receptors (deleted in colorectal cancer [DCC] and unc-5 netrin receptors A–D [UNC5A–D]) play essential roles for central nervous system (CNS) development, mediating axonal and neuronal navigation. Emerging evidence indicates that they are implicated in maintaining the adult brain structure and mediating the pathogenesis of Parkinson’s disease (PD). Recently, we reported the reduction of netrin-1 and brain-derived neurotrophic factor (BDNF) was inversely correlated with inflammatory cytokines-activated transcription factor CCAAT/enhancer binding protein β (C/EBPβ) in PD patient brains and colons. C/EBPβ binds to the promoters, repressing both netrin-1 and BDNF mRNA expression. Remarkably, netrin-1 deprivation triggered mammalian Ste20-like kinases 1 (MST1; Hippo) activation, which subsequently phosphorylated UNC5B and induced its apoptotic fragmentation via active caspase-3 in dopaminergic neurons in the substantia nigra (SN). Moreover, deficiency of netrin-1 stimulated activation of delta-secretase (asparagine endopeptidase [AEP]) that cleaves α-Syn at N103 and UNC5C receptor, facilitating PD pathologies. This review summarizes our current understanding of the crucial role of netrin-1 and its receptors in CNS and enteric nervous system contributing to PD pathologies by orchestrating multiple molecular players, including MST1, AEP, and C/EBPβ. These findings support that blockade of AEP or stimulation of netrin-1 signaling may provide an innovative disease-modifying therapeutic strategy for treating PD.

The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.