Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology.

Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer's disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3ß (GSK-3ß) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.

Exposure to alendronate is associated with a lower risk of bone metastases in osteoporotic women with early breast cancer.

BACKGROUND: Bisphosphonate (BP) treatment to prevent bone loss in breast cancer patients is already well established. However, data on the association between oral BP exposure before cancer diagnosis and disease outcomes in patients with early breast cancer are still scarce. Limited information is available on alendronate, the most common oral agent for the treatment of post-menopausal osteoporosis, regarding the association with bone metastases. AIM: To examine the association between oral bisphosphonate exposure before cancer diagnosis and the risk of bone metastases in osteoporotic women diagnosed with early breast cancer. SUBJECTS AND METHODS: This historical cohort study was conducted at the oncology division at Tel Aviv Medical Center. The study population included post-menopausal women with early breast cancer, diagnosed between 2002 and 2012. Data on cancer characteristics, diagnosis of osteoporosis, prior bisphosphonate exposure and outcome were collected from medical files. RESULTS: Among 297 osteoporotic women identified, 145 (49%) were treated with bisphosphonates (alendronate in 90% of the cases) before cancer diagnosis. BP-treated women were significantly older than the BP-naïve ones (67.9 years vs 64.6 years, p = 0.01), but comparable in risk factors and disease characteristics. Over a mean follow up of 5.6 years, nine cases of bone metastases were identified, eight of them among BP-naïve patient (cumulative incidence of 9.9%) and one among BP-treated patients (0.7%). In a multivariable Cox's proportional hazards survival model the use of BP prior to cancer diagnosis was associated with a hazard ratio of 0.04 (95%CI:0.004-0.403, p = 0.006) for bone metastasis. The HR remained similar after further adjustment for tumor stage and cancer therapy. CONCLUSIONS: History of alendronate use is associated with a lower likelihood of bone metastases in postmenopausal women with early breast cancer. Oral bisphosphonate treatment could be sufficient for reducing the risk of bone metastases.