Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairments

Alzheimer's disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking APOE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered significantly increase in the ApoE4 contents of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with adult healthy subjects. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum thyroid hormones level and cognitive function. We analysed effects of ApoE4 in peripheral exosomes on the neurological disorders in aged or thyroidectomied young mice. Ageing-associated hypothyroidism as well as acute thyreoidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activates NLRP3 inflammasome by increasing cholesterol level in neural cells. This, in turn, affects cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, which process can represent potential therapeutic target.

The Impact of Spironolactone on Markers of Myocardial Oxidative Status, Inflammation and Remodeling in Hyperthyroid Rats

Background: Hyperthyroidism promotes the development and progression of cardiovascular diseases (CVD). Aldosterone, a key mediator of myocardial inflammation, oxidative stress and fibrosis, may be activated in hyperthyroidism. Objective: To assess the impact of hyperthyroidism on aldosterone levels and myocardial oxidative status, inflammatory and fibrotic markers in hyperthyroid rats, and to test if the use of spironolactone (an aldosterone antagonist) attenuates these changes. Methods: Adult Wistar rats were randomly distributed into 4 groups; controls, spironolactone treated rats (Spir, 50mg/kg/day), hyperthyroid rats (Hyper, daily intraperitoneal levothyroxine 0.3mg/kg/day), and spironolactone treated hyperthyroid rats (Hyper+Spir) for 4 weeks. Blood pressure (Bp), and levels of serum and myocardial aldosterone, oxidants/antioxidants, inflammatory and fibrotic markers were measured. Result: Levothyroxine increased serum thyroid hormones and increased Bp, heart rate and heart to bodyweight ratio. Relative to control, serum aldosterone levels were increased in Hyper and Hyper+ Spir groups. In parallel, cardiac lipid peroxides and serum endothelin-1 were increased whereas cardiac superoxide dismutase, catalase, glutathione, and matrix metalloproteinase -2 were reduced in the Hyper group. Spironolactone decreased serum thyroid hormones and improved cardiac lipid peroxides and metalloproteinase -2 levels. The use of spironolactone decreased serum nitrite levels and increased cardiac SOD and glutathione. Cardiac levels of aldosterone, endothelin-1, transforming growth factor-beta and nitrite were similar among all groups. Conclusion: Hyperthyroid status was associated with an increase in aldosterone and oxidant/ inflammatory biomarkers. The use of spironolactone enhanced antioxidant defenses. Aldosterone antagonists may serve as potential drugs to attenuate the development of cardiac disease in hyperthyroidism.

Hypothyroidism and hyperprolactinemia in women with primary and secondary infertility

Background and objectives: Infertility is a global health problem including Bangladesh. Altered thyroid and prolactin levels have been implicated as a cause of infertility. The study was undertaken to find out the serum thyroid hormones and prolactin status in women with primary and secondary infertility. Methods: Women with primary and secondary infertility were enrolled. Fertile age-matched women were included as control. The anthropometric details (age, height and weight) were recorded. Overnight fasting blood sample was collected on 2nd day of menstrual cycle of the follicular phase. Serum thyroid stimulating hormone (TSH), free tri-iodothyronine (FT3) and free thyroxine (FT4) were measured by enzyme-linked immunosorbent assay (ELISA). Serum prolactin (PRL) was estimated by radioimmunoassay. Results: A total of 150 women were enrolled in the study. Out of 150 women, 50 had primary and 50 had secondary infertility while 50 women were age-matched fertile women as control. The mean TSH levels of both infertility groups were significantly higher than that of fertile women. Regarding thyroid function, 24% and 28% of women with primary and secondary infertility had hypothyroidism respectively. The serum prolactin level was high in 42.9% and 50% of hypothyroid cases in primary and secondary infertility groups respectively. Conclusion: The study has demonstrated high occurrence of hypothyroidism with raised serum prolactin levels among infertile females emphasizing the importance of estimating both serum TSH and prolactin in infertility. Ibrahim Med. Coll. J. 2020; 14(1): 41-46