Low androgenization index in elderly women and elderly men with Alzheimer’s disease

Paoletti, Anna Maria; Congia, S.; Lello, Stefano; Tedde, D.; Orrù, Marisa; Pistis, Marco; Pilloni, Monica; Zedda, Pierina; Loddo, Alessandro; Melis, G

doi:10.1212/01.wnl.0000094199.60829.f5

Cited by 94 publications

(77 citation statements)

References 10 publications

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“…In subsequent studies by this group, both total (Hogervorst et al, 2004;Hogervorst et al, 2003;Lehmann et al, 2004) and free (Hogervorst et al, 2002) testosterone levels were found to be significantly lower in men without AD irrespective of potentially confounding such indices as age, education, body mass index, smoking, alcohol use, diabetes, and hormone therapy. Similar findings of low testosterone in men with AD have been reported in several (Almeida et al, 2004;Moffat et al, 2004;Paoletti et al, 2004;Rasmuson et al, 2002;Watanabe et al, 2004) but not all (Pennanen et al, 2004) studies. Interestingly, low testosterone has also been linked to several other neurodegenerative diseases, including Parkinson's disease (Okun et al, 2004), vascular dementia (Watanabe et al, 2004), amyotropic lateral sclerosis (Militello et al, 2002), and Huntington's disease (Markianos et al, 2005).…”

Section: Age-related Androgen Depletion and Alzheimer's Diseasesupporting

confidence: 88%

Androgen cell signaling pathways involved in neuroprotective actions

Pike

Nguyen

Ramsden

et al. 2008

Hormones and Behavior

114

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As a normal consequence of aging in men, testosterone levels significantly decline in both serum and brain. Age-related testosterone depletion results in increased risk of dysfunction and disease in androgen-responsive tissues, including brain. Recent evidence indicates that one deleterious effect of age-related testosterone loss in men is increased risk for Alzheimer's disease (AD). We discuss recent findings from our laboratory and others that identify androgen actions implicated in protecting the brain against neurodegenerative diseases and begin to define androgen cell signaling pathways that underlie these protective effects. Specifically, we focus on the roles of androgens as (1) endogenous negative regulators of β-amyloid accumulation, a key event in AD pathogenesis, and (2) neuroprotective factors that utilize rapid non-genomic signaling to inhibit neuronal apoptosis. Continued elucidation of cell signaling pathways that contribute to protective actions of androgens should facilitate the development of targeted therapeutic strategies to combat AD and other agerelated neurodegenerative diseases.

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Section: Age-related Androgen Depletion and Alzheimer's Diseasesupporting

confidence: 88%

Androgen cell signaling pathways involved in neuroprotective actions

Pike

Nguyen

Ramsden

et al. 2008

Hormones and Behavior

114

View full text Add to dashboard Cite

show abstract

“…Prior work from several research groups including our own has linked both AD (Hogervorst et al 2001(Hogervorst et al , 2003Moffat et al 2004;Paoletti et al 2004;Rosario et al 2004) and elevated Ab levels (Gandy et al 2001; Gillett et al Fig. 7 DHT-induced decrease in Ab levels is dependent on an ARmediated pathway.…”

Section: Discussionmentioning

confidence: 85%

Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

Yao

Nguyen

Rosario

et al. 2008

Journal of Neurochemistry

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Age‐related testosterone depletion in men is a risk factor for Alzheimer’s disease. Prior studies suggest that androgens affect Alzheimer’s disease risk by regulating accumulation of β‐amyloid protein (Aβ) by an undefined mechanism. In this study, we investigated the role of the Aβ‐catabolizing enzyme neprilysin (NEP) in this process. First, we observed that androgens positively regulate neural expression of NEP in adult male rats. Next, we investigated androgen regulatory effects on both NEP expression and Aβ levels using cultured hippocampal neurons and neuronally differentiated rat pheochromocytoma cell 12 with or without androgen receptor (AR). Dihydrotestosterone (DHT) induced a time‐dependent increase in NEP expression. DHT also significantly decreased levels of Aβ in AR‐expressing cells transfected with amyloid precursor protein, but did not affect levels of either full‐length or non‐amyloidogenic, soluble amyloid precursor protein. Importantly, the DHT induced decrease of Aβ was blocked by pharmacological inhibition of NEP. The DHT‐mediated increase in NEP expression and decrease in Aβ levels were (i) not observed in rat pheochromocytoma cell 12 lacking AR and (ii) blocked in AR‐expressing cells by the antagonists, cyproterone acetate and flutamide. Together, these findings suggest that androgen regulation of Aβ involves an AR‐dependent mechanism requiring up‐regulation of the Aβ catabolizing enzyme NEP.

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“…The observation that estradiol levels control brain SHBG expression [24] also suggests that SHBG is involved in neuroendocrine control. Serum SHBG levels have been shown to increase in patients with Alzheimer’s disease [25, 26]. Further studies need to be done to demonstrate whether changes in central SHBG exist in various neurodegenerative ailments.…”

Section: Discussionmentioning

confidence: 99%

Identification of Sex Hormone-Binding Globulin in the Human Hypothalamus

et al. 2005

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Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin (SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin.

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Low androgenization index in elderly women and elderly men with Alzheimer’s disease

Cited by 94 publications

References 10 publications

Androgen cell signaling pathways involved in neuroprotective actions

Androgen cell signaling pathways involved in neuroprotective actions

Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

Identification of Sex Hormone-Binding Globulin in the Human Hypothalamus

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