Intraneuronal ß-amyloid impaired mitochondrial proteostasis through the impact on LONP1.

Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD. In this study, we identified LONP1, an ATP-dependent protease in the matrix, as a top Aß42 interacting mitochondrial protein through an unbiased screening and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m6A signaling contributed at least in part to Aß42-induced LONP1 reduction. Moreover, Aß42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aß and in the brain of CRND8 APP transgenic mice rescued Aß-induced mitochondrial deficits and cognitive deficits. These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a mechanism underlying intracellular Aß42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.

Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway.

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 ß-amyloid (Aß) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)--remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aß 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 Aß pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced Aß 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 Aß 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 Aß internalization within microglia. Together, these studies challenge the "frustrated phagocytosis" concept and suggest that neuronal-microglial communication link the two central AD pathologies.

Luteinizing hormone: Evidence for direct action in the CNS.

This article is part of a Special Issue "SBN 2014". 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.

Therapeutic benefits of central LH receptor agonism in the APP/PS1 AD model involve trophic and immune regulation and are reproductive status dependent.

The mechanisms that underly reproductive hormone effects on cognition, neuronal plasticity, and AD risk, particularly in relation to gonadotropin LH receptor (LHCGR) signaling, remain poorly understood. To address this gap in knowledge and clarify the impact of circulating steroid hormones on the therapeutic effects of CNS LHCGR activation, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV) and evaluated functional, structural, plasticity-related signaling cascades, Aß pathology, and transcriptome differences in reproductively intact and ovariectomized (OVX) APP/PS1 AD female mice. Here we demonstrate that CNS hCG delivery restored function to wild-type levels only in OVX APP/PS1 mice. Spine density was increased in all hCG treated groups independently of reproductive status. Notably, increases in BDNF signaling and cognition, were selectively upregulated only in the OVX hCG-treated group. RNA sequencing analyses identified a significant increase in peripheral myeloid and pro-inflammatory genes within the hippocampi of the OVX group that were completely reversed by hCG treatment, identifying a potential mechanism underlying the selective therapeutic effect of LHCGR activation. Interestingly, in intact mice, hCG administration mimicked the effects of gonadectomy. Together, our findings indicate that CNS LHCGR agonism in the post-menopausal context is beneficial through trophic and immune mechanisms. Our findings also underscore the presence of a steroid-LHCGR mechanistic interaction that is unexplored yet potentially meaningful to fully understand "post-menopausal" brain function and CNS hormone treatment response.

The LH receptor regulates hippocampal spatial memory and restores dendritic spine density in ovariectomized APP/PS1 AD mice.

Activation of the luteinizing hormone receptor (LHCGR) rescues spatial memory function and spine density losses associated with gonadectomy and high circulating gonadotropin levels in females. However, whether this extends to the AD brain or the mechanisms that underlie these benefits remain unknown. To address this question, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV), under reproductively intact and ovariectomized conditions to mimic the post-menopausal state in the APP/PS1mouse brain. Cognitive function was tested using the Morris water maze task, and hippocampal dendritic spine density, Aß pathology, and signaling changes associated with these endpoints were determined to address mechanisms. Here we show that central LHCGR activation restored function in ovariectomized APP/PS1 female mice to wild-type levels without altering Aß pathology. LHCGR activation increased hippocampal dendritic spine density regardless of reproductive status, and this was mediated by BDNF-dependent and independent signaling. We also show that ovariectomy in the APP/PS1 brain elicits an increase in peripherally derived pro-inflammatory genes which are inhibited by LHCGR activation. This may mediate reproductive status specific effects of LHCGR agonism on cognitive function and BDNF expression. Together, this work highlights the relevance of the LHCGR on cognition and its therapeutic potential in the "menopausal" AD brain.

Luteinizing hormone and the aging brain.

Fluctuations in luteinizing hormone (LH) release contribute to the development and maintenance of the reproductive system and become dysregulated during aging. Of note, increasing evidence supports extra-gonadal roles for LH within the CNS, particularly as it relates to cognition and plasticity in aging and age-related degenerative diseases such as Alzheimer's disease (AD). However, despite increasing evidence that supports a link between this hormone and CNS function, the mechanisms underlying LH action within the brain and how they influence cognition and plasticity during the lifespan is poorly understood and, in fact, often in conflict. This chapter aims to provide an up-to-date review of the literature addressing the role of LH signaling in the context of CNS aging and disease and put forward a unifying hypothesis that may explain currently conflicting theories regarding the role of LHCGR signaling in CNS function and dysfunction in aging and disease.

CNS luteinizing hormone receptor activation rescues ovariectomy-related loss of spatial memory and neuronal plasticity.

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 brain-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 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, intracerebroventricular 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.

Luteinizing Hormone Involvement in Aging Female Cognition: Not All Is Estrogen Loss.

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.

Hypothalamic-pituitary-gonadal axis involvement in learning and memory and Alzheimer's disease: more than "just" estrogen.

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.