Allopregnanolone levels are reduced in temporal cortex in patients with Alzheimer's disease compared to cognitively intact control subjects

Abstract

Background-The neurosteroid allopregnanolone has pronounced neuroprotective actions, increases myelination, and enhances neurogenesis. Evidence suggests that allopregnanolone dysregulation may play a role in the pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. Our prior data demonstrate that allopregnanolone is reduced in prefrontal cortex in male patients with AD compared to male cognitively intact control subjects, and inversely correlated with neuropathological disease stage (Braak and Braak). We therefore determined if allopregnanolone levels are also reduced in AD patients compared to control subjects in temporal cortex, utilizing a larger set of samples from both male and female patients. In addition, we investigated if neurosteroids are altered in subjects who are APOE4 allele carriers.

Neuroactive steroids, their metabolites, and neuroinflammation

“…The influence of the hormonal milieu on the etiopathogenesis of these conditions has been supported also by other observations done both in humans and animal models. Actually, changes in neuroactive steroid levels are evident in autopsy brain tissue from AD, PD, and MS patients (Naylor et al 2010, Luchetti et al 2011a,b, Noorbakhsh et al 2011; similarly significant modifications happen also in the CNS of PD and experimental autoimmune encephalomyelitis (EAE) models as well as of brain or spinal trauma (Labombarda et al 2006, Meffre et al 2007, 2012, Melcangi et al 2012. Moreover, the variation of hormonal levels in conditions such as castration, pregnancy, and the phase of estrous cycle may also influence the course of pathologies .…”

“…In particular, the observation that metabolites are i) more active than the precursor molecule , ii) appear to be necessary for some of the effects exerted by PROG or testosterone (Ghoumari et al 2003, Giachino et al 2003, Ciriza et al 2004, Djebaili et al 2004, He et al 2004, Pesaresi et al 2010a, Sun et al 2012, and iii) their synthesis is impaired in CNS diseases (Labombarda et al 2006, Meffre et al 2007, Caruso et al 2008, Naylor et al 2010, Pesaresi et al 2010b, Melcangi et al 2012 suggest that these molecules might share a higher therapeutic impact than classical hormones like PROG and testosterone.…”

Glycine and GABAA Ultra-Sensitive Ethanol Receptors as Novel Tools for Alcohol and Brain Research

“…To investigate the effects of endogenous neurosteroids on USERs, we tested two physiologically relevant concentrations of 3a,5a-THP (20 and 100 nM) on a1b2g2 GABA A Rs and a1 and g2 GABA A R USERs. The concentrations of 3a,5a-THP were based on findings describing 3a,5a-THP levels in the temporal cortex of postmortem brain tissue in cognitively intact patients ranging 5.644-32.11 ng/g (18-100 nM) (Naylor et al, 2010) and the highest concentration of serum 3a,5a-THP levels in pregnant women during the third trimester reported at 50 ng/ml (157 nM) (Luisi et al, 2000). Electrophysiological recordings were conducted according to the methods described earlier for ethanol application.…”

Lipids and Alzheimer's disease

“…Kolsch and colleagues provide data indicating levels of cholesterol and its precursors lanosterol, lathosterol and desmosterol are reduced in CSF derived from AD patients [28]. A study by Marx and colleagues focuses on the neurosteroids pregnenolone and dehydroepiandrosterone and show that both of these potentially neuroprotective molecules are reduced in AD temporal cortex as compared to control subjects [29].…”