Unintended effects of cardiovascular drugs on the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is rapidly becoming one of the leading causes of disability and mortality in the elderly. As life-expectancy increases, an increasing number of people will rely on modern medicines to treat age-associated disorders. Among these medications, some might benefit, while others might exacerbate, the pathogenesis of AD. We screened 1,600 FDA approved drugs for β-amyloid (Aβ)-modifying activity and identified drugs that can potentially influence amyloid precursor protein processing. In this study, we focused on cardiovascular drugs and demonstrated that some hypertensive medication can differentially modulate Aβ, both in vitro and in vivo. Our study suggests that some commonly prescribed drugs might exert unintended effects and modulate AD and provides the basis for continuing investigation of the role of individual drugs on a case-by-case basis. This line of investigation will lead to the identification of common medications that are potentially beneficial or detrimental to AD as a reference for physicians to consider when prescribing the most appropriate drugs for their patients, particularly for treating chronic disorders among the growing geriatric population

Effect of Caprylic triglyceride on food intake and lifespan of SOD1-G93A animals.

<p>(A) Food intake in SOD1-G93A animals treated with caprylic triglyceride (n = 18) or an isocaloric control diet (n = 17); (B) Mice in the two treatment groups (n = 11) were monitored daily and survival curve was plotted in GraphPad Prism.</p

Mitochondrial bioenergetic profile in the spinal cord of WT and SOD1 G93A mice on control or caprylic triglyceride diet.

<p>Mitochondria were isolated by differential centrifugation from the whole spinal cord of SOD1-G93A mice on control or caprylic triglyceride diet and oxygen consumption rates were analyzed using Seahorse XF24 extracellular flux analyzer. (A) A representative trace of OCR in the presence of pyruvate and malate. Adenosine diphosphate (ADP), oligomycin (O), carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and a mixture of rotenone, antimycin A, N,N,N’,N’-tetramethylphenylenediamine and ascorbate (RATA) were injected at the indicated time points to measure basal, state 3, state 4o, maximal and complex IV OCR as indicated. OCR in the presence of pyruvate and malate in (B) SOD1-G93A (ALS) and (D) wild type (WT) mice. (C) Spare respiratory capacity of mitochondria from WT and ALS mice on control or caprylic triglyceride diet. Data are mean ± SEM, n = 3 for all groups, *p<0.05 as compared to control by two-tailed student t-test.</p

Glucose tolerance, ketone, triglyceride and corticosterone levels following caprylic triglyceride treatment.

<p>(A) Fasting serum glucose level and (B) glucose tolerance test in SOD1-G93A animals on control or caprylic triglyceride; (C) Blood ketone level at pre-symptomatic (10 weeks) or post-symptomatic (17 weeks) stage; (D) Plasma total triglyceride levels. (E) Plasma corticosterone level. All data are mean ± SEM, n = 4–5 for (A, B), n = 5 for (C) and n = 6–7 for (D, E) *p<0.05 by two-tailed t-test).</p

Nissl-stained motor neuron count in the lumbar spinal cord.

<p>(A) Representative photomicrographs of Nissl-stained sections at the ventral horn area of the lumbar spinal cord; (B) Motor neuron counts. Data are mean ± SEM, n = 3–4 per group, *p<0.05 by two-tailed t-test.</p

Schematic diagram of primary screening of 1600 FDA approved drugs.

<p>Schematic diagram of primary screening of 1600 FDA approved drugs.</p

Effect of Aβ-lowering drug treatment on blood pressure and amyloid neuropathology in Tg2576 mice.

<p>(A–F) Measurements of systolic, diastolic blood pressure, and mean arterial blood pressure (MAP) and heart beat (pulse) in response to ∼4 weeks of drug treatments. (G-L) Assessment of Aβ1-42 and Aβ1-40 peptide concentrations in the brain of drug treated mice <i>vs.</i> the control mice. (M-R) Assessment of Aβ1-42 and Aβ1-40 in peripheral blood of drug treated mice <i>vs.</i> the control mice. Blood pressure determination for each animal was calculated as the mean of 10 individual measurements. Values represents group mean values (<u>+</u>SEM); n = 3–5 mice per group. **P<0.01, *P<0.05, 2-tailed student t-test.</p

Effect of short-term in vivo on body weight and liquid consumption in Tg2576 mice.

<p>Animals were treated with the anti-hypertensive drugs for four weeks and body weight and liquid consumption were monitored weekly. Data presented here are the end point body weight and the average liquid consumption throughout the study.</p>*<p>P<0.05, 2-tailed student t-test, n = 3–5 for each treatment group.</p

Effect of Aβ -promoting drugs treatment on blood pressure and amyloid neuropathology in Tg2576 mice.

<p>(A and D) Measurements of systolic, diastolic blood pressure, and mean arterial blood pressure (MAP) in response to ∼4 weeks of drug treatments. (B and E) Assessment of Aβ1-42 and Aβ1-40 peptide concentrations in the brain of drug treated mice <i>vs.</i> the control mice. (C and F) Assessment of Aβ1-42 and Aβ1-40 in peripheral blood of drug treated mice <i>vs.</i> the control mice. Values represents group mean values (±SEM); n = 3–5 mice per group. **P<0.01, *P<0.05, 2-tailed student t-test.</p