The Neuroprotective Effect Of Decreased Luteinizing Hormone On Astrocytic Pathology In An Alzheimer's Disease Model


After menopause or ovariectomy (ovx) females have high levels of luteinizing hormone (LH) which may contribute to and exacerbate Alzheimer’s disease (AD). High levels of LH have been associated with decreased spatial memory and increased amyloid-beta levels, both characteristic of Alzheimer’s disease. Conversely, by decreasing levels of this hormone, studies have been able to improve the memory of normal, nonAD rats and recover memory deficits in animal models of AD. Based on this research, it was hypothesized that female rats with low, as compared to high, levels of LH would show less hippocampal damage in an animal model of AD. To create an Alzheimer’s disease model, the neurotoxins amyloid-beta and ibotenic acid were infused into the hippocampus of female Sprague-Dawley rats. To vary LH levels, rats were either ovx so they had high LH levels or were ovx and given Antide, a GnRH antagonist that decreases LH levels. Antide or vehicle were administered either 1d before (early Antide) or beginning 4d after (late Antide) the neurotoxin infusion. This resulted in 4 groups of ovx females: Control, AD, AD + early Antide, and AD + late Antide. Damage was ascertained using immunocytochemistry for glial fibrillary acidic protein (GFAP), an intermediate filament protein specific to astrocytes of the central nervous system. Astrocytic pathology within the CA1 region of the hippocampus was determined by the number of GFAP immunoreactive cells, astrocyte cell size, and GFAP content (area covered by stained pixels). Ovx AD females had an increased number of GFAP-containing cells, increased astrocytic cell size, and increased GFAP content compared to ovx control animals. Early Antide treatment prior to neurotoxin infusion resulted in a decreased cell number and a decreased GFAP content compared to the AD group. Furthermore, while AD+late Antide treatment had no effect on cell number compared to the AD females, it did result in decreased GFAP content. Lastly, cell size for both Antide treatment groups was intermediate between the AD and control groups. These results provide evidence that low levels of LH results in decreased neural damage in CA1 in an AD model. This suggests that high levels of LH such as those seen after menopause are harmful to the hippocampus and may contribute to the damage seen during AD, and that an LH antagonist could play either a preventative and/or therapeutic role in the treatment of Alzheimer’s disease.


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