Implication of lipoprotein lipase-deficient impaired learning and memory: focus on aging and testosterone deficiency

摘要

OBJECTIVE Normal male aging is associated with declines in levels of the sex steroid hormone testosterone. A large body of evidence supports a neurotrophic role for testosterone in central nervous system. Lipoprotein lipase(LPL) is also expressed in the brain with highest levels found in the pyramidal cells of the hippocampus, we previous reported LPL-deficient mice exhibited memory disfunction. Testosterone is known to be largelyconverted to estradiol following aromatization within the hippocampus. Although testosterone has been implicated in lipid metabolism, it remains elusive whether testosterone can regulate brain LPL through DNA methylation mechanism. In order to clarify DNA methylation control exerted by testosterone over LPL gene in central nervous system, and its effect on lipid metabolism, we examined the adult male rat hippocampus to determine whether castration induced testosterone deficiency can affect lipid profile and LPL gene expression through its altered methylation pattern. METHODS Model of aging with declines in levels of the sex steroid hormone testosterone was performed as our previous description. RESULTS(1) Serum testosterone and brain testosterone levels were significantly decreased, which were restored to the control level after testosterone replacement,respectively(P<0.01);(2) Androgen deficiency was not found in Morris water maze and motor performance, however, androgen deficiency increases neurological and cognitive impairment in aged rats.(3)Decreased expression of olfactory marker protein(OMP) in olfactory bulb of SD rats treated with androgen deficiency.(4) The expression of Fox O3 and OMP in the olfactory bulb of androgen deficient rats was down-regulated, accompanied by dysfunction of the olfactory limbic system.(5) Decreased LPL m RNA level and inversely increased LPL promoter methylation level were observed following androgen deficiency and reserved by testosterone replacement.(6) In contrast, androgen deficiency slightly increased estrogen receptor beta(ERβ) m RNA levels and significantly decreased its promoter methylation levels within the hippocampus, and reserved as well by testosterone replacement. CONCLUSION(1) LPL in synaptic plasticity and contributes to a better understanding of the LPL function in the brain, where altered LPL levels are related to learning and memory impairment.(2) Androgen and Fox O3 play an important role in the olfactory cognitive process of the nervous system.(3) LPL expression in hippocampus is actively maintained by sex steroid hormones and that DNA methylation modification may contribute to this homeostatic regulation.