The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease

Abstract

Sex hormones are the physiological factors that regulate neurogenesis during embryogenesis and continuing through adulthood. These hormones support the formation of brain structures such as dendritic spines, axons and synapses required for the capture of information (memories). Intriguingly, a recent animal study has demonstrated that induction of neurogenesis results in the loss of previously encoded memories in animals (e.g. infantile amnesia). In this connection, much evidence now indicates that Alzheimer’s disease (AD) also involves aberrant re-entry of post-mitotic neurons into the cell cycle. Cell cycle abnormalities appear very early in the disease, prior to the appearance of plaques and tangles, and explain the biochemical, neuropathological and cognitive changes observed with disease progression. Since sex hormones control when and how neurons proliferate and differentiate, the endocrine dyscrasia that accompanies menopause and andropause is a key signaling event that impacts neurogenesis and the acquisition, processing, storage and recall of memories. Here we review the biochemical, epidemiological and clinical evidence that alterations in endocrine signaling with menopause and andropause drive the aberrant re-entry of post-mitotic neurons into an abortive cell cycle with neurite retraction that leads to neuron dysfunction and death. When the reproductive axis is in balance, luteinizing hormone (LH), and its fetal homolog, human chorionic gonadotropin (hCG), promote pluripotent human and totipotent murine embryonic stem cell and neuron proliferation. However, strong evidence supports menopausal/andropausal elevations in the ratio of LH:sex steroids as driving aberrant mitotic events mediated by the upregulation of tumor necrosis factor, amyloid-β precursor protein processing towards the production of mitogenic Aβ, and the activation of Cdk5, a key regulator of cell cycle progression and tau phosphorylation (a cardinal feature of both neurogenesis and neurodegeneration). Cognitive studies also demonstrate the negative consequences of a high LH:sex steroid ratio on human cognitive performance. Prospective epidemiological and clinical evidence in humans supports lowering the ratio of circulating gonadotropins-GnRH to sex steroids in reducing the incidence of AD and halting cognitive decline. Together, these data support endocrine dyscrasia and the subsequent loss of cell cycle control as an important etiological event in the development of neurodegenerative diseases including AD, stroke and Parkinson’s disease.

Evidence of altered depression and dementia‐related proteins in the brains of young rats after ovariectomy

“…Previous studies support the idea that multiple factors involved in menopause-induced brain damage, for example, synapse loss, neuronal loss, blood-brain barrier disruptions, white matter degeneration, and so on (Atwood and Bowen 2015;Kantarci et al 2018). Thus, considerable changes after menopause must be more rigorously considered.…”

Conjugated Linoleic Acid Administration Induces Amnesia in Male Sprague Dawley Rats and Exacerbates Recovery from Functional Deficits Induced by a Controlled Cortical Impact Injury

“…Hypogonadotropic hypogonadism as a result of acute (≤ 80% of cases) and/or chronic (~40% of cases) TBI could therefore greatly compromise neuroregeneration and recovery from a TBI. In this respect, it is well recognized that the endocrine dyscrasia that results from menopause and during andropause has a negative impact on cognitive function, and that hormone supplementation with physiological human sex steroids can halt or reverse the cognitive decline associated with aging [ 16 , 17 ]. These data indicate the need to develop strategies to rebalance the HPG hormones following TBI.…”

A Unified Hypothesis of Early- and Late-Onset Alzheimer’s Disease Pathogenesis

“…Preclinical studies have demonstrated the efficacy of increasing sex steroids and suppressing gonadotropins in reversing neurodegeneration and cognitive decline in animal models of AD (reviewed in [98, 184]). Preclinical studies in mouse models of AD also have demonstrated that specific inhibitors of the cell cycle, such as the oral administration of the synthetic retinoid X receptor-selective retinoid bexarotene, stimulates the rapid reversal of cognitive, social, and olfactory deficits, improves neural circuit function and enhances the clearance of soluble Aβ within hours in an apolipoprotein E-dependent manner [185, 186].…”