The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer’s Disease

Marx, Christine E.; Trost, William T.; Shampine, Lawrence J.; Stevens, Robert; Hulette, Christine M.; Steffens, David C.; Ervin, John F.; Butterfield, Marian I.; Blazer, D; Massing, Mark W.; Lieberman, Jeffrey A.

doi:10.1016/j.biopsych.2006.06.017

Cited by 132 publications

(98 citation statements)

References 87 publications

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“…In middle-aged rat hippocampus, the average concentration of several peptide growth factors, FGF-2, IGF1, and VEGF are substantially lower relative to that in young rat hippocampus (12). Consistent with a decline in growth factors, a significant decrease in APα was evident in aged and AD brains (9)(10)(11). Interestingly, APα in the 3xTgAD mouse plasma and cortex was consistently lower in the 3xTgAD mouse compared with the non-Tg.…”

Section: Discussionmentioning

confidence: 80%

“…Parallel to the diminution in neurogenesis, is the decline of neurosteroids in the aging and AD brain (9)(10)(11)(12)(13). Consistent with a decline in growth factors (10,12,13), APα content is significantly lower in aged subjects (9) and in brains of AD patients compared with age-matched controls (10,11). In contrast, during fetal development when neural progenitor proliferation is maximal, APα is synthesized throughout the embryonic period and in pluripotential progenitor cells (5,14).…”

mentioning

confidence: 95%

“…Though the regenerative potential of the mammalian brain is sustained throughout the life span, proliferative capacity of neural progenitors declines with age and diseases, such Alzheimer's disease (AD) (8). Parallel to the diminution in neurogenesis, is the decline of neurosteroids in the aging and AD brain (9)(10)(11)(12)(13). Consistent with a decline in growth factors (10,12,13), APα content is significantly lower in aged subjects (9) and in brains of AD patients compared with age-matched controls (10,11).…”

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confidence: 99%

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Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Wang

Singh²,

Liu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

236

266

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Our previous analyses showed that allopregnanolone (APα) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APα to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between APα-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by FACS for BrdU+ cells. Learning and memory function was assessed using the hippocampal-dependent trace eye-blink conditioning paradigm. At 3 months, basal level of BrdU+ cells in the SGZ of 3xTgAD mice was significantly lower relative to non-Tg mice, despite the lack of evident AD pathology. APα significantly increased, in a dose-dependent manner, BrdU+ cells in SGZ in 3xTgAD mice and restored SGZ proliferation to normal magnitude. As with the deficit in proliferation, 3xTgAD mice exhibited deficits in learning and memory. APα reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APα-induced survival of neural progenitors was significantly correlated with APα-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Aβ, may contribute to the cognitive phenotype of AD, and that APα could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease.

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Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 95%

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confidence: 99%

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Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Wang

Singh²,

Liu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

236

266

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“…It may be that some of these differences in prevalence of AD are related to differences in these steroids among women and men, and with aging (reviewed by Bernardi et al 2004;Seeman 1997). In support of this idea, among subjects with AD, there are lower levels of a P 4 metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP) in serum (Bernardi et al 2000), and prefrontal cortex measured postmortem (Marx et al 2006). Lower plasma 3α,5α-THP levels in those with AD or non-AD dementia, compared to controls, may be a biomarker for AD (Smith et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Progesterone reduces depression-like behavior in a murine model of Alzheimer’s Disease

Frye

Walf

2009

AGE

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Although anxiety and depression are not the core symptoms of Alzheimer's Disease (AD), there are changes observed in mood in those with AD, as well as in the aging population. Anxiety and depression may be influenced by progesterone P 4 and/or its neuroactive metabolites, dihydroprogesterone (DHP) and 5α-pregnan-3α-ol-20-one (3α,5α-THP). To begin to investigate progestogens' role in AD, a double transgenic mouse model of early-onset familial AD that cooverexpresses mutant forms of amyloid precursor protein (APPswe) and presenilin 1 Δ exon 9 mutation was utilized. As such, the effects of long-term (from 6 to 12 months of age) administration of P 4 to ovariectomized (ovx) wildtype and APPswe+PSEN1Δe9 mice for changes in affective behavior was investigated. APPswe+PSEN1Δ9 mutant mice had increased anxiety-like (i.e., increased emergence latencies, decreased time spent on the open quadrants of the elevated zero maze) and increased depressive-like behavior (i.e., increased time spent immobile) than did wildtype mice. Compared to vehicle-administration, P 4 administration (which produced physiological circulating P 4 , DHP, and 3α,5α-THP levels, particularly in the wildtype mice) decreased depressant-like behavior in the forced swim test. These effects occurred independent of changes in general motor behavior/coordination, pain threshold, and plasma corticosterone levels. Thus, the APPswe+PSEN1Δ9 mutation alters affective behavior, and P 4 treatment reversed depressive-like behavior.

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“…Similarly to what has been observed in CNS [65][66][67][68], in peripheral nerves, the levels of neuroactive steroids are also modified by trauma or pathology. In a crush injury model, the levels of PREG and P metabolites (DHP and THP) evaluated by liquid chromatography-tandem mass spectrometry in the sciatic nerve are decreased by trauma [69].…”

Section: Sexually Dimorphic Changes Of Neuroactive Steroid Levels Indmentioning

confidence: 53%

Neuroactive Steroids and Peripheral Neuropathy

Melcangi

Giatti

Pesaresi

et al. 2011

Hormones in Neurodegeneration, Neuroprotection, and Neurogenesis

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Peripheral neuropathy, either inherited or acquired, is a very common disorder for which effective clinical treatments are not yet available. Neuroactive steroids such as progesterone, testosterone, and their reduced metabolites represent a promising therapeutic option for peripheral neuropathy. Peripheral nerves are able to synthesize and metabolize neuroactive steroids and are a target for these molecules since they express classical and nonclassical steroid receptors. Neuroactive steroids modulate the expression of key transcription factors (TFs) for Schwann cell function, regulate Schwann cell proliferation, and promote the expression of myelin proteins. Interestingly, they are also able to counteract biochemical, morphological, and functional alterations of peripheral nerves in different experimental models of neuropathy, including the alterations caused by aging, diabetic neuropathy, and physical injury. Therefore, neuroactive steroids and pharmacological agents that are able to increase their local synthesis and the synthetic ligands for their receptors offer a promising potential for the treatment of different forms of peripheral neuropathy.

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The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer’s Disease

Cited by 132 publications

References 87 publications

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Progesterone reduces depression-like behavior in a murine model of Alzheimer’s Disease

Neuroactive Steroids and Peripheral Neuropathy

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