Protective actions of sex steroid hormones in Alzheimer’s disease

Abstract

Risk for Alzheimer’s disease (AD) is associated with age-related loss of sex steroid hormones in both women and men. In postmenopausal women, the precipitous depletion of estrogens and progestogens is hypothesized to increase susceptibility to AD pathogenesis, a concept largely supported by epidemiological evidence but refuted by some clinical findings. Experimental evidence suggests that estrogens have numerous neuroprotective actions relevant to prevention of AD, in particular promotion of neuron viability and reduction of β-amyloid accumulation, a critical factor in the initiation and progression of AD. Recent findings suggest neural responsiveness to estrogen can diminish with age, reducing neuroprotective actions of estrogen and, consequently, potentially limiting the utility of hormone therapies in aged women. In addition, estrogen neuroprotective actions are also modulated by progestogens. Specifically, continuous progestogen exposure is associated with inhibition of estrogen actions whereas cyclic delivery of progestogens may enhance neural benefits of estrogen. In recent years, emerging literature has begun to elucidate a parallel relationship of sex steroid hormones and AD risk in men. Normal age-related testosterone loss in men is associated with increased risk to several diseases including AD. Like estrogen, testosterone has been established as an endogenous neuroprotective factor that not only increases neuronal resilience against AD-related insults, but also reduces β- amyloid accumulation. Androgen neuroprotective effects are mediated both directly by activation of androgen pathways and indirectly by aromatization to estradiol and initiation of protective estrogen signaling mechanisms. The successful use of hormone therapies in aging men and women to delay, prevent, and or treat AD will require additional research to optimize key parameters of hormone therapy and may benefit from the continuing development of selective estrogen and androgen receptor modulators.

Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M)

“…32,33 In addition, testosterone showed to have a neuroprotective role in animal studies, 34,35 and some studies have shown protective actions of sex hormones in several neurodegenerative diseases. 36 Regarding the HSD17B1 gene, although we did not found an effect in AO variation, this does not exclude other variants in other estradiollinked genes as possible modifier candidate genes in FAP ATTRV30M.…”

Cellular and Molecular Mechanisms of the Effects of Sex Hormones on the Nervous System

“…Androgens may regulate the production and the levels of Aβ, by a classic genomic mechanism and rapid non-genomic signaling or via aromatization to estradiol and activation of estrogen pathways [81,82]. Testosterone can attenuate the toxicity of Aβ in cultured hippocampal neurons via a rapid, estrogen-independent mechanism [83].…”

Cyclic E2 and P4 on Alzheimer’s Disease Pathways

“…However, these subsequent dysfunctions are characteristic of aging effects due to loss of hormones and its effect on mitochondria in both women and men, which has been widely documented in the literature [30]- [36]. This is why we focus on the effects produced by steroid hormones due to their ability to control and regulate gene protein products.…”

“…As discussed in Pike et al [30], estrogen's neuro-protective actions are modulated by progesterone [51] [52], whereas static progesterone exposure always inhibits estrogen's actions, synthetic or otherwise. However, the cyclic delivery of P4 and E2 will allow for the increase of E2 receptors [48] [49].…”