A key event in the pathogenesis of Alzheimer’s disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. We found that lansoprazole enhances Aβ37, Aβ40 and Aβ42 production and lowers Aβ38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Aβ40 levels in brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.

The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may indicate heterodimerization of these receptors. Therefore, this study investigated the molecular and functional interplay between MAS and the AT2R. Molecular interactions were assessed by fluorescence resonance energy transfer and by cross correlation spectroscopy in human embryonic kidney-293 cells transfected with vectors encoding fluorophore-tagged MAS or AT2R. Functional interaction of AT2R and MAS was studied in astrocytes with CX3C chemokine receptor-1 messenger RNA expression as readout. Coexpression of fluorophore-tagged AT2R and MAS resulted in a fluorescence resonance energy transfer efficiency of 10.8 ± 0.8%, indicating that AT2R and MAS are capable to form heterodimers. Heterodimerization was verified by competition experiments using untagged AT2R and MAS. Specificity of dimerization of AT2R and MAS was supported by lack of dimerization with the transient receptor potential cation channel, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked by an AT2R antagonist (PD123319) and also by a MAS antagonist (A-779). Knockout of a single of these receptors made astrocytes unresponsive for both agonists. Our results suggest that MAS and the AT2R form heterodimers and that-at least in astrocytes-both receptors functionally depend on each other.

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Background: Major prevention trials for Alzheimer's disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In two cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-beta and tau deposits.Methods: Some 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD cohort) underwent amyloid and tau positron emission tomography (PET) and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the Dominantly Inherited AD (DIAN) cohort with amyloid PET and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results:In PREVENT-AD, lower neuroticism, neuropsychiatric burden and higher education were associated with less amyloid deposition (p=0.014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p=0.006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p=0.005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions:In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multi-domain interventions might help delay AD onset or progression.

Objectives AT 2 R defi ciency exacerbates atherosclerotic progression in ApoE (-/-) mice. Because AT 2 Rs are low/undetectable in wild-type (WT) C57BL/6 aortas we hypothesize that ApoE regulates vascular AT 2 Rs. MethodsWe measured AT 2 Rs (using quantitative-immunofl uorescence) in aortic arch vascular smooth muscle (VSMC) and endothelial cell (EC) layers and mean arterial blood pressure (MAP) in anesthetized mice. Nine-week-old ApoE (-/-) and WT mice were fed a low (LC) or high cholesterol (HC) diet for 1 week. Animals were administered vehicle or Ang II (12 g/kg/hr), with or without PD123319 (10 mg/kg/day) (AT 2 R antagonist) for 7 days. ResultsIn LC/ApoE (-/-) vs. WT mice, VSMC and EC AT 2 R was 80-and 26-fold higher (P Ͻ 0.001). HC increased serum cholesterol ~2-fold (P Ͻ 0.001) and decreased VSMC AT 2 R levels 9.5-fold (P Ͻ 0.01) in ApoE (-/-) mice. Low-dose Ang II infusion, which was without effect in LC/WT mice decreased MAP by 15% in LC/ApoE (-/-) (79 Ϯ 2 vs. 67 Ϯ 3 mmHg, vehicle vs. Ang II, respectively; n ϭ 10/gp., P Ͻ 0.01) but not HC/ ApoE (-/-) mice (82 Ϯ 3 vs. 80 Ϯ 2 mmHg vehicle vs. Ang II, respectively; n ϭ 7-11/gp.). A study of vasodilator mechanisms indicated that lowdose Ang II caused a ~6-fold increase in VSMC, but not EC, PPAR-␥ (P Ͻ 0.001) in LC/ApoE (-/-) mice; both VSMC and EC phospho-nitric oxide synthase were not signifi cantly changed. These effects were blocked by PD123319.Methods Male spontaneously hypertensive rats (SHRs) were divided into six groups and treated transiently with three injections of vehicle or AT1 receptor vaccine (0.1 mg) at age 4, 6 and 8 weeks, or continuously with candesartan cilexetil (0.1 mg/kg/day) or hydralazine hydrochloride (5 mg/kg/day), then administered NG-nitro-Larginine methyl ester (L-NAME) from age 18 to 21 weeks to induce renal injury. ResultsVaccination against the AT1 receptor caused a signifi cant increase in AT1 receptor titers, and a sustained decrease in BP. L-NAME