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

Abstract

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.

Improvement of neuronal bioenergetics by neurosteroids: Implications for age-related neurodegenerative disorders

“…Progesterone, and its 3α-5α-derivate allopregnanolone (or 3α, 5α-tetrahydroprogesterone) as well as 3α-androstanediol, seem to play a role in mood modulation. Their therapeutic potential for the treatment of depression, anxiety [53][54][55] and more recently AD is currently under investigation [35]. In the present study, we demonstrated that progesterone increased ATP levels and MMP without significant effects on basal respiration in neuroblastoma cells (Fig.…”

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

“…Baseline differences were not observed in cortically-mediated tasks (object recognition or T maze) between the mouse strains, and progesterone improved performance of both wild-type and APPswe-PSEN1Δe9 mice in both of these tasks (156, 157; Figure 2). Additionally, progesterone, compared to vehicle, increased progesterone and 3α,5α-THP in the cortex of both wild-type and APPswe+PSEN1Δe9, but only increased 3α,5α-THP in the hippocampus of wild-type mice (156, 157). Thus, these data suggest that progesterone does not improve APPswe-PSEN1Δe9 behaviour in hippocampally-mediated tasks, like that of wild-type mice, and that they also show deficiencies in their capacity to form 3α,5α-THP in the hippocampus.…”

“…We, and others, have shown that people in the early stages of Alzheimer's disease or dementia have lower circulating levels of 3α,5α-THP than do non-demented peers matched for age, gender, education and socioeconomic factors (154). We have also used a double transgenic mouse model of early-onset familial Alzheimer's disease that co-overexpresses mutant forms of amyloid precursor protein and presenilin 1 Δ exon 9 mutation (APPswe+PSEN1Δe9; (155-157)). Comparisons were made following ovariectomy at 6 months of age and administration of chronic subcutaneous pellets of placebo (cholesterol) or progesterone for 6 months.…”

“…In this mouse model, genetic mutations cause them to develop β-amyloid deposits after 5 months of age, and by 9 months old severe plaque deposits build up in the cortex and hippocampus (155). APPswe+PSEN1Δe9, compared to wild-type mice, had poorer performance on hippocampally-mediated tasks (worse object placement performance and more depressive behaviour in the forced swim task); progesterone improved responding in the wild-type, but not the APPswe+PSEN1e9, mice in these tasks (156, 157; Figure 2). Baseline differences were not observed in cortically-mediated tasks (object recognition or T maze) between the mouse strains, and progesterone improved performance of both wild-type and APPswe-PSEN1Δe9 mice in both of these tasks (156, 157; Figure 2).…”

“…APPswe+PSEN1Δe9, compared to wild-type mice, had poorer performance on hippocampally-mediated tasks (worse object placement performance and more depressive behaviour in the forced swim task); progesterone improved responding in the wild-type, but not the APPswe+PSEN1e9, mice in these tasks (156, 157; Figure 2). Baseline differences were not observed in cortically-mediated tasks (object recognition or T maze) between the mouse strains, and progesterone improved performance of both wild-type and APPswe-PSEN1Δe9 mice in both of these tasks (156, 157; Figure 2). Additionally, progesterone, compared to vehicle, increased progesterone and 3α,5α-THP in the cortex of both wild-type and APPswe+PSEN1Δe9, but only increased 3α,5α-THP in the hippocampus of wild-type mice (156, 157).…”