Search

Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-beta protein precursor (AbetaPP) and are reported to stimulate the activity of alpha-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the alpha-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in alpha-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates alpha-secretase activity. Treatment of human neuroblastoma cells with 50 microM zaragozic acid resulted in a approximately 3 fold increase of alpha-secretase activity and reduced cellular cholesterol by approximately 30%. These effects were comparable to results obtained from cells treated with a low lovastatin concentration (2 microM). Zaragozic acid-stimulated secretion of alpha-secretase-cleaved soluble AbetaPP was dose dependent and saturable. Lovastatin- or zaragozic acid-stimulated increase of alpha-secretase activity was completely abolished by a selective ADAM10 inhibitor. By targeting the alpha-secretase ADAM10 to lipid raft domains via a glycosylphosphatidylinositol anchor, we demonstrate that ADAM10 is unable to cleave AbetaPP in a cholesterol-rich environment. Our results indicate that inhibition of cholesterol biosynthesis by a low lovastatin concentration is sufficient for alpha-secretase activation. [ABSTRACT FROM AUTHOR]

Background: Research concerning people living with dementia (PwD) and their informal caregivers (ICs) has recently begun to focus on dyadic aspects of psychosocial interventions., Objective: We adapted a dyadic psychosocial intervention and examined its effects on psychobiological stress in daily life., Methods: Twenty-four PwD-caregiver dyads were visited seven times at home by specialized nursing staff. Momentary subjective stress, salivary cortisol (sCort), and salivary alpha-amylase (sAA) were measured in PwD and ICs before and after each home visit as well as six times per day at two days each at the beginning and end of the intervention as part of an ambulatory assessment. Hair cortisol concentrations (HCC) were measured twice., Results: After each home visit session, ICs reported lower subjective stress. sCort was lower in both ICs and PwD, whereas sAA did not change. In daily life, area under the curve (AUCg) concerning sCort secretion indicated that PwD had lower sCort daily output at the end of the intervention, and AUCg concerning subjective stress indicated that both PwD and ICs reported lower subjective stress than at the beginning of the intervention. AUCg concerning sAA did not change over time in either group. HCC did not vary over time but increased with disease severity., Conclusion: The psychosocial intervention reduced psychobiological stress but affected psychobiological stress measures differently in PwD and ICs. In particular, the discrepancy between subjective and physiological markers of stress in PwD emphasizes the added value to evaluate treatment success and understand underlying mechanisms as a complement to self-reports.

Apolipoprotein A1 (ApoA1) is the major protein component of the high-density lipoprotein and involved in cholesterol transport. Disruption of cholesterol homeostasis has been identified as a contributing factor for Alzheimer's disease (AD). Moreover, polymorphisms of ApoA1 have been associated with higher risk of disease onset and cognitive decline. Therefore, ApoA1 has been suggested as a biomarker in AD. Here, we tested a small cohort of AD and non-AD dementia patients and measured levels of ApoA1 in cerebrospinal fluid. Our results indicate that ApoA1 might not be applicable to distinguish AD from other forms of dementia., Competing Interests: The authors have no conflict of interest to report., (© 2020 – IOS Press and the authors. All rights reserved.)

The regulation of physiological gut functions such as peristalsis or secretion of digestive enzymes by the central nervous system via the Nervus vagus is well known. Recent investigations highlight that pathological conditions of neurological or psychiatric disorders might directly interfere with the autonomous neuronal network of the gut - the enteric nervous system, or even derive from there. By using a murine Alzheimer's disease model, we investigated a potential influence of disease-associated changes on gastrointestinal properties. 5xFAD mice at three different ages were compared to wild type littermates in regard to metabolic parameters and enzymes of the gut by fluorimetric enzyme assay and western blotting. Overexpression of human amyloid-β protein precursor (AβPP) within the gut was assessed by qPCR and IHC; fecal microbiome analysis was conducted by 16SrRNA quantitation of selected phyla and species. While general composition of fecal samples, locomotion, and food consumption of male 5xFAD animals were not changed, we observed a reduced body weight occurring at early pathological stages. Human AβPP was not only expressed within the brain of these mice but also in gut tissue. Analysis of fecal proteins revealed a reduced trypsin amount in the 5xFAD model mice as compared to the wild type. In addition, we observed changes in fecal microbiota composition along with age. We therefore suggest that the presence of the mutated transgenes (AβPP and PS1), which are per se the basis for the genetic form of Alzheimer's disease in humans, directly interferes with gut function as shown here for the disease model mice.

ADAM10 is one of the key players in ectodomain-shedding of the amyloid-β protein precursor (AβPP). Previous research with postmortem tissue has shown reduced expression and activity of ADAM10 within the central nervous system (CNS) of Alzheimer's disease (AD) patients. Determination of cerebral ADAM10 in living humans is hampered by its transmembrane property; only the physiological AβPP cleavage product generated by ADAM10, sAβPPα, can be assessed in cerebrospinal fluid. Establishment of surrogate markers in easily accessible material therefore is crucial. It has been demonstrated that ADAM10 is expressed in platelets and that platelet amount is decreased in AD patients. Just recently it has been shown that platelet ADAM10 and cognitive performance of AD patients positively correlate. In contrast to AD patients, to our knowledge almost no information has been published regarding ADAM10 expression during normal aging. We investigated ADAM10 amount and activity in platelets of cognitively healthy individuals from three different age groups ranging from 22-85 years. Interestingly, we observed an age-dependent increase in ADAM10 levels and activity in platelets.