Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD-extracellular deposition of ␤-amyloid (A␤) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)-remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on A␤ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of A␤ pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced A␤ deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of A␤ and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and A␤ internalization within microglia. Together, these studies challenge the "frustrated phagocytosis" concept and suggest that neuronal-microglial communication link the two central AD pathologies.

Accumulating studies affirm the effects of age-related endocrine dysfunction on cognitive decline and increasing risk of neurodegenerative diseases. It is well known that estrogens can be protective for cognitive function, and more recently androgens and luteinizing hormone have also been shown to modulate learning and memory. Understanding the mechanisms underlying hypothalamic–pituitary–gonadal axis-associated cognitive dysfunction is crucial for therapeutic advancement. Here, we emphasize that reproductive hormones are influential in maintaining neuronal health and enhancing signaling cascades that lead to cognitive impairment. We summarize and critically evaluate age-related changes in the endocrine system, their implications in the development of Alzheimer’s disease, and the therapeutic potential of endocrine modulation in the prevention of age-related cognitive decline.

Hormonal dysfunction due to aging, especially during menopause, plays a substantial role in cognitive decline as well as the progression and development of neurodegenerative diseases. The hypothalamic-pituitary-gonadal (HPG) axis has long been implicated in changes in behavior and neuronal morphology. Most notably, estrogens have proven beneficial in the healthy brain through a host of different mechanisms. Recently, luteinizing hormone (LH) has emerged as a candidate for further investigation for its role in the CNS. The basis of this is that both LH and the LH receptor are expressed in the brain, and serum levels of LH correlate with cognitive deficits and Alzheimer's disease (AD) incidence. The study of LH in cognition and AD primarily focuses on evaluating the effects of downregulation of this peptide. This literature has shown that decreasing peripheral LH, through a variety of pharmacological interventions, reduces cognitive deficits in ovariectomy and AD models. However, few studies have researched the direct actions of LH on neurons and glial cells. Here we summarize the role of luteinizing hormone in modulating cognition, and we propose a mechanism that underlies a role for brain LH in this process.

Pervasive age-related dysfunction in hypothalamic-pituitary-gonadal (HPG) axis is associated with cognitive impairments in aging as well as pathogenesis of age-related neurodegenerative diseases such as the Alzheimer's disease (AD). As a major regulator of the HPG axis, the steroid hormone estrogen has been widely studied for its role in regulation of memory. Although estrogen modulates both cognition as well as cognition associated morphological components in a healthy state, the benefits of estrogen replacement therapy on cognition and disease seem to diminish with advancing age. Emerging data suggests an important role for luteinizing hormone (LH) in CNS function, which is another component of the HPG axis that becomes dysregulated during aging, particularly in menopause. The goal of this review is to highlight the current existing literature on LH and provide new insights on possible mechanisms of its action.

Ovariectomy (OVX), a menopause model, leads to cognition and neuronal plasticity deficits that are rescued by estrogen administration or downregulation of pituitary luteinizing hormone (LH). LH is present in the brain. However, whether LH levels differ across brain regions, change across reproductive stages, or whether CNS-specific LHR signaling play a role in OVX-related cognitive and neuroplasticity losses is completely unknown. To address this, we measured brain LH in cycling and OVX C57Bl/6 across brain regions and determined whether OVX-related functional and plasticity deficits could be rescued by intracerebroventricular (ICV) administration of the LHR agonist (hCG). Here, we show that while pituitary LH is increased in OVX, brain LH is decreased, primarily in spatial memory and navigation areas. Furthermore, ICV hCG delivery after OVX rescued dendritic spine density and spatial memory. In vitro, we show that hCG increased neurite outgrowth in primary hippocampal neurons in a receptor specific manner. Taken together, our data suggest that loss of brain LH signaling is involved in cognitive and plasticity losses associated with OVX and loss of ovarian hormones.