Exercise and estrogen: common pathways in Alzheimer's disease pathology.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by progressive declines in cognitive function. Current epidemiological data indicate significant sex-linked disparities, where females have a higher risk of developing AD compared with male counterparts. This disparity necessitates further investigations to uncover the pathological and molecular factors influencing these sex differences. Although the underlying pathways behind this observed disparity remain elusive, recent research points to menopausal estrogen loss as a potential factor. Estrogen holds a significant role in amyloid precursor protein (APP) processing and overall neuronal health through the regulation of brain-derived neurotrophic factor (BDNF), a factor that is also reduced in postmenopausal women. BDNF is a known contributor to neuronal health and its reduced expression is typically linked to AD disorders. Exercise is known to increase BDNF and may provide an accessible activity for postmenopausal women to reduce their risk of AD. This review aims to discuss the relationship between estrogen, exercise, and BDNF in AD pathology.

Examining the effects of ovarian hormone loss and diet-induced obesity on Alzheimer's disease markers of amyloid-ß production and degradation.

After menopause, women experience declines in ovarian sex hormones, an event that has recently been associated with increased amyloid-ß peptides, a main feature of Alzheimer's disease. Diet-induced insulin resistance also increases amyloid-ß peptides; however, whether this process is exacerbated with ovarian sex hormone loss remains unknown. Female C57BL6/J mice received either bilateral ovariectomy (OVX; n = 20) or remained intact (n = 20) at 24 wk of age and were placed on either a low- or high-fat diet (LFD, n = 10 for OVX and intact; HFD, n = 10 for OVX and intact) for 10 wk. Independently, OVX led to increases in the amyloidogenic marker, soluble amyloid precursor protein ß (sAPPß). The HFD in combination with OVX led to lower insulin degrading enzyme (IDE) protein content and activity in the prefrontal cortex, indicative of decreased amyloid-ß degradation; however, no differences in amyloid-ß content were observed. Data from this study provide novel evidence of independent effects of peripheral insulin resistance and ovarian sex hormone loss in decreasing brain markers of amyloid-ß degradation. Furthermore, findings indicate how the loss of ovarian sex hormones can promote the formation of amyloidogenic APP cleavage products, independent of diet-induced insulin resistance.NEW & NOTEWORTHY This study provides novel insight into the effect of peripheral insulin resistance and ovarian hormone loss in decreasing brain markers of amyloid-ß degradation. Results demonstrate that ovarian hormone loss through ovariectomy increased the amyloidogenic marker, sAPPß, while the high-fat diet in combination with ovariectomy led to lower IDE protein content and activity in the prefrontal cortex, indicative of decreased amyloid-ß degradation. These original results provide important information for future targets in early AD pathogenesis.

Characterization of Alzheimer's disease-like neuropathology in Duchenne's muscular dystrophy using the DBA/2J mdx mouse model.

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder caused by a mutation in the dystrophin gene. In addition to muscle pathology, some patients with DMD will exhibit cognitive impairments with severity being linked to age and type of genetic mutation. Likewise, some studies have shown that mdx mice display impairments in spatial memory compared with wild-type (WT) controls, while others have not observed any such effect. Most studies have utilized the traditional C57BL/10 (C57) mdx mouse, which exhibits a mild disease phenotype. Recently, the DBA/2J (D2) mdx mouse has emerged as a more severe and perhaps clinically relevant DMD model; however, studies examining cognitive function in these mice are limited. Thus, in this study we examined cognitive function in age-matched C57 and D2 mdx mice along with their respective WT controls. Our findings show that 8- to 12-week-old C57 mdx mice did not display any differences in exploration time when challenged with a novel object recognition test. Conversely, age-matched D2 mdx mice spent less time exploring objects in total as a well as less time exploring the novel object, suggestive of impaired recognition memory. Biochemical analyses of the D2 mdx brain revealed higher soluble amyloid precursor protein ß (APPß) and APP in the prefrontal cortex of mdx mice compared with WT, and lower soluble APPα in the hippocampus, suggestive of a shift towards amyloidogenesis and a similar pathogenesis to Alzheimer's disease. Furthermore, our study demonstrates the utility of the D2 mdx model in studying cognitive impairment.

Examination of BDNF Treatment on BACE1 Activity and Acute Exercise on Brain BDNF Signaling.

Perturbations in metabolism results in the accumulation of beta-amyloid peptides, which is a pathological feature of Alzheimer's disease. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate limiting enzyme responsible for beta-amyloid production. Obesogenic diets increase BACE1 while exercise reduces BACE1 activity, although the mechanisms are unknown. Brain-derived neurotropic factor (BDNF) is an exercise inducible neurotrophic factor, however, it is unknown if BDNF is related to the effects of exercise on BACE1. The purpose of this study was to determine the direct effect of BDNF on BACE1 activity and to examine neuronal pathways induced by exercise. C57BL/6J male mice were assigned to either a low (n = 36) or high fat diet (n = 36) for 10 weeks. To determine the direct effect of BDNF on BACE1, a subset of mice (low fat diet = 12 and high fat diet n = 12) were used for an explant experiment where the brain tissue was directly treated with BDNF (100 ng/ml) for 30 min. To examine neuronal pathways activated with exercise, mice remained sedentary (n = 12) or underwent an acute bout of treadmill running at 15 m/min with a 5% incline for 120 min (n = 12). The prefrontal cortex and hippocampus were collected 2-h post-exercise. Direct treatment with BDNF resulted in reductions in BACE1 activity in the prefrontal cortex (p < 0.05), but not the hippocampus. The high fat diet reduced BDNF content in the hippocampus; however, the acute bout of exercise increased BDNF in the prefrontal cortex (p < 0.05). These novel findings demonstrate the region specific differences in exercise induced BDNF in lean and obese mice and show that BDNF can reduce BACE1 activity, independent of other exercise-induced alterations. This work demonstrates a previously unknown link between BDNF and BACE1 regulation.

Exercise Intensity and Recovery on Circulating Brain-derived Neurotrophic Factor.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) is an exercise-induced neurotropin mediating neuroprotection and synaptic plasticity. Although exercise intensity is implicated as a potentially important mediator of BNDF release after exercise, the optimal exercise stimulus (interval vs continuous) and intensity (submaximal vs supramaximal) for augmenting circulating BDNF levels remains unknown. Irisin, an exercise-driven myokine, may also contribute to neuroprotection by upregulating BDNF. PURPOSE: To examine the response and recovery of plasma BDNF and irisin after acute exercise of differing intensities. METHODS: Eight males (23.1 ± 3.0 yr of age; V˙O2max 51.2 ± 4.4 mL·kg·min) completed four acute exercise sessions: 1) moderate-intensity continuous training (MICT, 65% V˙O2max); 2) vigorous-intensity continuous training (VICT, 85% V˙O2max); 3) sprint interval training (SIT, "all out"); and 4) no exercise (CTRL). Blood was collected preexercise as well as immediately, 30 min, and 90 min postexercise. Plasma BDNF and irisin were assessed with commercially available enzyme-linked immunosorbent assay kits. RESULTS: Plasma BDNF levels increased immediately after exercise in the SIT group (P < 0.0001) with plasma concentrations recovering 30 and 90 min postexercise. The BDNF levels after MICT were reduced 30 min postexercise compared with immediately postexercise (P = 0.0189), with no other changes across time points in MICT and VICT groups. Plasma BDNF area under the curve in SIT was significantly higher compared with CTRL, MICT, and VICT (P = 0.0020). No changes in plasma irisin across exercise groups and time points were found (P > 0.9999). CONCLUSIONS: Plasma BDNF levels increased in an intensity-dependent manner with SIT eliciting the highest BDNF concentration immediately postexercise. These results identify SIT as a time-efficient exercise modality to promote brain health through BDNF release.

Interleukin-6 Treatment Results in GLUT4 Translocation and AMPK Phosphorylation in Neuronal SH-SY5Y Cells.

Interleukin-6 (IL-6) is a pleiotropic cytokine that can be released from the brain during prolonged exercise. In peripheral tissues, exercise induced IL-6 can result in GLUT4 translocation and increased glucose uptake through AMPK activation. GLUT4 is expressed in the brain and can be recruited to axonal plasma membranes with neuronal activity through AMPK activation. The aim of this study is to examine if IL-6 treatment: (1) results in AMPK activation in neuronal cells, (2) increases the activation of proteins involved in GLUT4 translocation, and (3) increases neuronal glucose uptake. Retinoic acid was used to differentiate SH-SY5Y neuronal cells. Treatment with 100 nM of insulin increased the phosphorylation of Akt and AS160 (p < 0.05). Treatment with 20 ng/mL of IL-6 resulted in the phosphorylation of STAT3 at Tyr705 (p ≤ 0.05) as well as AS160 (p < 0.05). Fluorescent Glut4GFP imaging revealed treatment with 20ng/mL of IL-6 resulted in a significant mobilization towards the plasma membrane after 5 min until 30 min. There was no difference in GLUT4 mobilization between the insulin and IL-6 treated groups. Importantly, IL-6 treatment increased glucose uptake. Our findings demonstrate that IL-6 and insulin can phosphorylate AS160 via different signaling pathways (AMPK and PI3K/Akt, respectively) and promote GLUT4 translocation towards the neuronal plasma membrane, resulting in increased neuronal glucose uptake in SH-SY5Y cells.

Acute exercise and brain BACE1 protein content: a time course study.

Obesity and insulin resistance are risk factors in the development of neurodegenerative disorders. Previous work suggests that one acute bout of exercise may have beneficial neuro-protective effects in obese mice. The rate limiting enzyme in the production of amyloid-beta peptides, BACE1, was reduced in the prefrontal cortex 2 h post-exercise, however if these effects remain over time is unknown. We aimed to determine how long exercise-induced alterations persist in the prefrontal cortex and hippocampus following a single exercise bout. Male C57BL/6J mice were fed either a low (LFD, 10% kcals from lard) or a high fat diet (HFD, 60% kcals from lard) for 7 weeks. HFD mice then underwent an acute bout of treadmill running (15 m/min, 5% incline, 120 min) followed by 2-, 8-, or 24-h of recovery. The HFD increased body mass (LFD 27.8 ± 1.05 vs. HFD 41.7 ± 0.60 g; P < 0.05) and glucose intolerance (AUC LFD 63.27 ± 4.5 vs. HFD 128.9 ± 4.6; P < 0.05). Prefrontal cortex BACE1 content was reduced 2- and 8-h post-exercise compared to sedentary HFD mice, however BACE1 protein content at 24 h was not different. Hippocampal BACE1 content was reduced 8- and 24-h post-exercise. Compared to the LFD, the HFD had higher prefrontal cortex phosphorylation of p38, JNK, and AMPK, indicative of increased neuronal stress. Post-exercise prefrontal cortex p38 and JNK phosphorylation were no different between the HFD or LFD groups, while ERK phosphorylation was significantly reduced by 24 h. The HFD increased JNK phosphorylation in the hippocampus. These results demonstrate the direct and potent effects of exercise on reducing BACE1 prefrontal cortex and hippocampal content. However the reduction in prefrontal cortex BACE1 content is short lived.

Female Sex Hormones and Cardiac Pressure Overload Independently Contribute to the Cardiogenic Dementia Profile in Yucatan Miniature Swine.

Post-menopausal women with heart failure (HF) frequently exhibit cardiogenic dementia. Using a pre-clinical swine model of post-menopausal HF, we recently demonstrated that experimental menopause (ovariectomy; OVX) and HF (6-month cardiac pressure overload/aortic banding; AB) independently altered cerebral vasomotor control and together impaired cognitive function. The purpose of this study was to examine the prefrontal cortex and hippocampus tissues from these animals to assess whether OVX and HF are associated with neurologic alterations that may contribute to cardiogenic dementia. We hypothesized that OVX and HF would independently alter neuronal cell signaling in swine with post-menopausal cardiogenic dementia. Immunoblot analyses revealed OVX was associated with reduced estrogen receptor-α in both brain regions and HF tended to exacerbate OVX-induced deficits in the hippocampus. Further, OVX was associated with a reduction in the ratio of phosphorylated:total Akt and ERK in the hippocampus as well as decreased total Akt and synaptophysin in the prefrontal cortex. In contrast, HF was associated with a trend toward reduced phosphorylated:total ERK in the prefrontal cortex. In addition, HF was associated with decreased ß-amyloid (1-38) in the prefrontal cortex and increased ß-amyloid (1-38) in the hippocampus. Regional brain lipid analysis revealed OVX tended to increase total, saturated, and monounsaturated fatty acid content in the prefrontal cortex, with the greatest magnitude of change occurring in the AB-OVX group. The data from this study suggest that OVX and HF are independently associated with regional-specific neurologic changes in the brain that contribute to the cardiogenic dementia profile in this model. This pre-clinical swine model may be a useful tool for better understanding post-menopausal cardiogenic dementia pathology and developing novel therapies.

Increased Prevalence of Obesity/Type 2 Diabetes and Lower Levels of Lithium in Rural Texas Counties May Explain Greater Alzheimer's Disease Risk.

BACKGROUND/OBJECTIVE: To compare Alzheimer's disease (AD) mortality rates and coinciding risk factors in rural and urban Texas populations. METHODS: 155 Texas counties were divided into 73 rural and 82 urban areas using the U.S. Census Bureau definition of rurality. Changes in age-adjusted AD mortality across these counties were calculated using a 7-year aggregation model from 2000-2006 and 2009-2015. Data pertaining to gender, race, education, obesity, diabetes, physical inactivity, and lithium concentrations in tap water were also collected from readily available databases. RESULTS: Change in age-adjusted AD mortality was higher in rural counties (9.5±1.4) versus urban (5.9±1.1) over the time period examined. Similarly, obesity (30.2±0.2% ), diabetes (11.0±0.1% ), and physical inactivity (29.4±0.2% ) levels were significantly higher in rural populations compared to urban (29.1±0.2%, 9.7±0.1%, and 26.7±0.3, respectively). In contrast, the percent of population with some college education (40.1±0.7% ) was lower compared to urban (29.4±0.2% and 44.4±0.9%, respectively). Lithium concentrations in tap water was significantly lower in rural counties compared to urban (63.3±8.2 and 33.4±4.7µg/L, respectively). No significant differences were observed among females and however, we did find significant differences in the percent of African American and Hispanics. Correlational analysis uncovered a negative association between education status and AD mortality over time (r = -0.17). Further analysis controlling for physical inactivity, education, and trace lithium concentrations results in a loss of statistical significance. CONCLUSIONS: AD mortality rates are higher in rural counties when compared to urban counties, and this may be linked to greater physical inactivity, obesity, and diabetes, as well as lower trace lithium levels in tap water.