Amisulpride as a potential disease-modifying drug in the treatment of tauopathies.

INTRODUCTION: Hyperphosphorylation and aggregation of the microtubule-associated protein tau cause the development of tauopathies, such as Alzheimer's disease and frontotemporal dementia (FTD). We recently uncovered a causal link between constitutive serotonin receptor 7 (5-HT7R) activity and pathological tau aggregation. Here, we evaluated 5-HT7R inverse agonists as novel drugs in the treatment of tauopathies. METHODS: Based on structural homology, we screened multiple approved drugs for their inverse agonism toward 5-HT7R. Therapeutic potential was validated using biochemical, pharmacological, microscopic, and behavioral approaches in different cellular models including tau aggregation cell line HEK293 tau bimolecular fluorescence complementation, primary mouse neurons, and human induced pluripotent stem cell-derived neurons carrying an FTD-associated tau mutation as well as in two mouse models of tauopathy. RESULTS: Antipsychotic drug amisulpride is a potent 5-HT7R inverse agonist. Amisulpride ameliorated tau hyperphosphorylation and aggregation in vitro. It further reduced tau pathology and abrogated memory impairment in mice. DISCUSSION: Amisulpride may be a disease-modifying drug for tauopathies.

Dementia in Germany: epidemiology, trends and challenges.

Background: Dementia poses a growing challenge for individuals, healthcare, social support, and society amidst the ongoing ageing of populations. To evaluate the care requirements and social implications of dementia in Germany, reliable statistics regarding its current and future occurrence are necessary. Methods: Using existing data sources and recent research results, this paper compiles and analyses relevant statistics on the occurrence of dementia in Germany, presents protective and risk factors, and options for care provision. Results: Recent projections indicate a potential surge in the number of dementia patients in Germany, predicted to rise from 1.7 million at present to up to 3.0 million by the year 2070. Cognitive and motor deterioration and behavioural changes associated with dementia lower the ability to live independently. These changes are often tied to social exclusion and stigma and, particularly in the severe phase of the disease, necessitate extensive medical and care requirements. This contributes to dementia being one of the most costly diseases at old age from an overall societal perspective. Currently, there are no curative treatment options available. Conclusions: To reduce the increase in the number of dementia patients and associated costs in the future, preventive approaches, particularly promoting a healthy lifestyle, may prove effective. Simultaneously, the healthcare system, society, and caregivers must prepare for the increasing number of dementia patients. Improved diagnostics, new forms of therapy, and social innovations that support those who are affected and their relatives can help reduce the burden of dementia and its associated costs.

Sporadic Use of Antibiotics in Older Adults and the Risk of Dementia: A Nested Case-Control Study Based on German Health Claims Data.

BACKGROUND: Antibiotics for systemic use may increase the risk of neurodegeneration, yet antibiotic therapy may be able to halt or mitigate an episode of neurodegenerative decline. OBJECTIVE: To investigate the association of sporadic use of antibiotics and subsequent dementia risk (including Alzheimer's disease). METHODS: We used data from the largest public health insurance fund in Germany, the Allgemeine Ortskrankenkasse (AOK). Each of the 35,072 dementia cases aged 60 years and older with a new dementia diagnosis during the observation period from 2006 to 2018 was matched with two control-patients by age, sex, and time since 2006. We ran conditional logistic regression models for dementia risk in terms of odds ratios (OR) as a function of antibiotic use for the entire antibiotic group and for each antibiotic subgroup. We controlled for comorbidities, need for long-term care, hospitalizations, and nursing home placement. RESULTS: Antibiotic use was positively associated with dementia (OR = 1.18, 95% confidence interval (95% CI):1.14-1.22), which became negative after adjustment for comorbidities, at least one diagnosis of bacterial infection or disease, and covariates (OR = 0.93, 95% CI:0.90-0.96). Subgroups of antibiotics were also negatively associated with dementia after controlling for covariates: tetracyclines (OR = 0.94, 95% CI:0.90-0.98), beta-lactam antibacterials, penicillins (OR = 0.93, 95% CI:0.90-0.97), other beta-lactam antibacterials (OR = 0.92, 95% CI:0.88-0.95), macrolides, lincosamides, and streptogramins (OR = 0.88, 95% CI:0.85-0.92), and quinolone antibacterials (OR = 0.96, 95% CI:0.92-0.99). CONCLUSION: Our results suggest that there was a decreased likelihood of dementia for preceding antibiotic use. The benefits of antibiotics in reducing inflammation and thus the risk of dementia need to be carefully weighed against the increase in antibiotic resistance.