Human studies suggest either a protective role or no benefit of statins against the development of Alzheimer's disease (AD). We tested the hypothesis that statin-mediated cholesterol reduction in aged dogs, which have cognitive impairments and amyloid-β (Aβ) pathology, would improve cognition and reduce neuropathology. In a study of 12 animals, we treated dogs with 80 mg/day of atorvastatin for 14.5 months. We did not observe improvements in discrimination learning; however, there were transient impairments in reversal learning, suggesting frontal dysfunction. Spatial memory function did not change with treatment. Peripheral levels of cholesterol, LDLs, triglycerides, and HDL were significantly reduced in treated dogs. Aβ in cerebrospinal fluid and brain remained unaffected. However, β-secretase-1 (BACE1) protein levels and activity decreased and correlated with reduced brain cholesterol. Finally, lipidomic analysis revealed a significant decrease in the ratio of omega-6 to omega-3 essential fatty in temporal cortex of treated aged dogs. Aged beagles are a unique model that may provide novel insights and translational data that can predict outcomes of statin use in human clinical trials. Treatment with atorvastatin may be beneficial for brain aging by reducing BACE1 protein and omega6:omega3 ratio, however, the potential adverse cognitive outcomes reported here should be more carefully explored given their relevance to human clinical outcomes.
Accumulation of amyloid-β (Aβ) plays an important role in Alzheimer's disease (AD) pathology. There is growing evidence that disordered sleep may accelerate AD pathology by impeding the physiological clearance of Aβ from the brain that occurs in normal sleep. Therapeutic strategies for improving sleep quality may therefore help slow disease progression. It is well documented that the composition and dynamics of sleep are sensitive to ambient temperature. We therefore compared Aβ pathology and sleep metrics derived from polysomnography in 12-month-old female 3xTg-AD mice (n = 8) exposed to thermoneutral temperatures during the light period over 4 weeks to those of age- and sex-matched controls (n = 8) that remained at normal housing temperature (22°C) during the same period. The treated group experienced greater proportions of slow wave sleep (SWS)-i.e. epochs of elevated 0.5-2 Hz EEG slow wave activity during non-rapid eye movement (NREM) sleep-compared to controls. Assays performed on mouse brain tissue harvested at the end of the experiment showed that exposure to thermoneutral temperatures significantly reduced levels of DEA-soluble (but not RIPA- or formic acid-soluble) Aβ40 and Aβ42 in the hippocampus, though not in the cortex. With both groups pooled together and without regard to treatment condition, NREM sleep continuity and any measure of SWS within NREM at the end of the treatment period were inversely correlated with DEA-soluble Aβ40 and Aβ42 levels, again in the hippocampus but not in the cortex. These findings suggest that experimental manipulation of SWS could offer useful clues into the mechanisms and treatment of AD.
Human exposure to heavy metals is a major public health problem that could occur either during the course of everyday life or while working in hazardous occupations. Heavy metals, like lead (Pb), are responsible for cognitive and behavioral deficits in children as well as in adults and may be a significant contributor to age-related neurologic dysfunction. Cerebrovascular pathology is a significant co-morbidity in all the forms of age-related dementia, including AD. Most individuals with AD have some degree of comorbid cerebrovascular pathology, although individuals with a history of obesity and T2DM have substantial amount of this pathology. The role of Pb exposure at different times of lifespan and the impact on neuropathology and cognitive function have been evaluated in a novel mouse model of neurologic disease. The db/AD mouse becomes rapidly obese and diabetic, and develops AD-related pathology and cerebrovascular abnormalities with increasing age. Db/AD mice were exposed to low (0.004%) or high (0.2%) concentration of Pb up to 30 days from either E14, birth or in adulthood via drinking water and concentration of Pb in the blood and brain measured by ICP-MS. Expression of AD-related genes was determined by two-step qRT-PCR, Aβ was measured by ELISA, and AD-protein levels were measured by Western or spot blot. Glucose tolerance tests (GTT) and blood pressure (BP) were evaluated in another cohort of mice (3-4 months old), treated with 0.2%-Pb starting at birth. Cognitive performance was evaluated in spontaneous alternation and forced Y-Maze, Morris Water Maze (MWM) and anxiety by Elevated Plus Maze (EPM) test. Some mice also underwent MRI scans. Pb had no effect on body weight, survival and health effects; substantial quantities of Pb were present in both blood and brain. APP, BACE1, PEN2 genes showed different changes depending on the age of Pb exposure. No acute effects were observed on GTT, BP, cognitive tests, EPM and MRI. We have not observed an effect of Pb immediately and for several months post-exposure. However, we expect that effects on neuropathology and behavior will only appear with increasing of age, particularly at the higher concentration. Funding provided by NIEHS (ES024158), NINDS (NS083692), and NIA (AG045809).
