17α-Estradiol Attenuates Neuron Loss in Ovariectomized Dtg AβPP/PS1 Mice

Abstract

Quantitative microanalysis of brains from patients with Alzheimer's disease (AD) find neuronal loss and neuroinflammation in structures that control cognitive function. Though historically difficult to recapitulate in experimental models, several groups have recently reported that by middle-age, transgenic mice that co-express high levels of two AD-associated mutations, amyloid-β protein precursor (AβPPswe) and presenilin 1 (PS1ΔE9), undergo significant AD-type neuron loss in sub-cortical nuclei with heavy catecholaminergic projections to the hippocampal formation. Here we report that by 13 months of age these dtg AβPPswe/PS1ΔE9 mice also show significant loss of pyramidal neuron in a critical region for learning and memory, the CA1 subregion of hippocampus, as a direct function of amyloid-β (Aβ) aggregation. We used these mice to test whether 17α-estradiol (17αE2), a less feminizing and non-carcinogenic enantiomer of 17β-estradiol, protects against this CA1 neuron loss. Female dtg AβPPswe/PS1ΔE9 mice were ovariectomized at 8–9 months of age and treated for 60 days with either 17αE2 or placebo via subcutaneous pellets. Computerized stereology revealed that 17αE2 ameliorated the loss of neurons in CA1 and reduced microglial activation in the hippocampus. These findings support the view that 17αE2, which may act through non-genomic mechanisms independent of traditional estrogen receptors, could prevent or delay the progression of AD in older men and women.

Non-feminizing estrogens: A novel neuroprotective therapy

“…The beneficial effects of 17α-E2 on Aβ levels were observed without the detrimental, superphysiological uterotrophic response observed following 17β-E2 treatment (Levin-Allerhand et al, 2002). Similarly, in estrogen-depleted APP SWE xPS1 mice, 17α-E2 attenuated the loss of neurons in CA1 and reduced microglial activation in the hippocampus (Manaye et al, 2011). When injected directly into the hippocampus of young, estrogen-depleted rats, the non-feminizing synthetic estrogen analogues, ZYC-5 and ZYC-13, increased cognitive performance to a similar extent as 17β-E2 (Walf et al, 2011), suggesting non-feminizing estrogens may have functional effects on memory in addition to their neuroprotective effects.…”

Intraneuronal APP and extracellular Aβ independently cause dendritic spine pathology in transgenic mouse models of Alzheimer’s disease

“…To recapitulate the pathogenesis of human AD, APP23 mouse model overexpresses human APP with the Swedish mutation under the murine Thy1 promoter [ 57 ], while deltaE9 mice express APP with the Swedish mutation controlled by mouse prion protein promoter elements together with mutant human PS1 lacking exon 9, which is associated with familial AD [ 29 , 52 ]. Although these two transgenic mouse models display neuronal loss, cholinergic deficit, cognitive impairments, amyloid plaques and neuroinflammation in old age, the onsets of amyloid plaque formation and cognitive decline between them are very different in early adulthood [ 5 , 8 , 9 , 30 , 38 , 56 ]. Aβ deposits are not observed in APP23 mice younger than 6 months, but age-matched deltaE9 mice have already developed plaques [ 28 ].…”

Progesterone increased β-endorphin innervation of the locus coeruleus , but ovarian steroids had no effect on noradrenergic neurodegeneration

“…However, healthy brains do not appear to lose NE neurons during the natural aging process (Ohm et al, 1997). Manaye and colleagues (2011) described a neuroprotective role of estradiol in which this hormone attenuated the neuronal loss in the hypothalamus of ovariectomized rats in a rodent model of AD. Nonetheless, no studies have shown a neuroprotective effect of estradiol and progesterone in the LC, although there is evidence that the onset of menopause, characterized by the decline of ovarian steroids, can lead to anxiety and depression (Solomon & Herman, 2009; Warren, 2007), both related to alterations in NE neurotransmission.…”