Steroids and Alzheimer’s Disease: Changes Associated with Pathology and Therapeutic Potential

Abstract

<jats:p>Alzheimer’s disease (AD) is a multifactorial age-related neurodegenerative disease that today has no effective treatment to prevent or slow its progression. Neuroactive steroids, including neurosteroids and sex steroids, have attracted attention as potential suitable candidates to alleviate AD pathology. Accumulating evidence shows that they exhibit pleiotropic neuroprotective properties that are relevant for AD. This review focuses on the relationship between selected neuroactive steroids and the main aspects of AD disease, pointing out contributions and gaps with reference to sex differences. We take into account the regulation of brain steroid concentrations associated with human AD pathology. Consideration is given to preclinical studies in AD models providing current knowledge on the neuroprotection offered by neuroactive (neuro)steroids on major AD pathogenic factors, such as amyloid-β (Aβ) and tau pathology, mitochondrial impairment, neuroinflammation, neurogenesis and memory loss. Stimulating endogenous steroid production opens a new steroid-based strategy to potentially overcome AD pathology. This article is part of a Special Issue entitled Steroids and the Nervous System.</jats:p>

Insights into Disease-Associated Tau Impact on Mitochondria

“…Decreased levels of neurosteroids were observed in AD brains [ 150 , 151 , 152 ]. In particular, the levels of the neurosteroids pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulfate (DHEAS) were significantly reduced in the striatum, hypothalamus and cerebellum of AD patients compared to non-demented controls (postmortem analysis) [ 150 ].…”

Predictive Modeling of Multiplex Chemical Phenomics for Novel Cells and Patients: Applied to Personalized Alzheimer’s Disease Drug Repurposing

“…We found cyclin, that controls the modulation of neurotransmitter, steriod, and cell cycle related pathways are enriched in genes from subgroup 1, subgroup 2, and subgroup 3, respectively. Previous research has shown the dysregulation of cyclin and steroid is related to AD 66,67 . The re-entry of cell cycle in neuronal cell could be the cause of AD 68 .…”

Promising Intervention Approaches to Potentially Resolve Neuroinflammation And Steroid Hormones Alterations in Alzheimer’s Disease and Its Neuropsychiatric Symptoms

“…Different lines of evidence showed that AD can significantly alter neurosteroidogenesis [ 12 ] and substantial changes in their levels have been observed in the AD brain. As summarized in [ 12 , 80 ], allopregnanolone was found to be significantly decreased in the prefrontal and temporal cortices of AD patients [ 81 - 83 ]. A general trend toward decreased levels of progesterone was observed in all AD patients' brain regions (frontal cortex, striatum, hypothalamus and hippocampus) compared with controls [ 84 ].…”

“…Interestingly, DHEAS or estrogens administration was shown to improve cognitive performance in different AD animal models [ 12 ]. Changes in sex steroid levels are also relevant to AD [ 80 ]. Women with AD aged 80 years and older exhibited significantly lower brain 17β-estradiol than age-matched nondemented controls [ 90 , 91 ].…”