Targeting impaired adult hippocampal neurogenesis in ageing by leveraging intrinsic mechanisms regulating Neural Stem Cell activity.

Deficits in adult neurogenesis may contribute to the aetiology of many neurodevelopmental, psychiatric and neurodegenerative diseases. Genetic ablation of neurogenesis provides proof of concept that adult neurogenesis is required to sustain complex and dynamic cognitive functions, such as learning and memory, mostly by providing a high degree of plasticity to neuronal circuits. In addition, adult neurogenesis is reactive to external stimuli and the environment making it particularly susceptible to impairment and consequently contributing to comorbidity. In the human brain, the dentate gyrus of the hippocampus is the main active source of neural stem cells that generate granule neurons throughout life. The regulation and preservation of the pool of neural stem cells is central to ensure continuous and healthy adult hippocampal neurogenesis (AHN). Recent advances in genetic and metabolic profiling alongside development of more predictive animal models have contributed to the development of new concepts and the emergence of molecular mechanisms that could pave the way to the implementation of new therapeutic strategies to treat neurological diseases. In this review, we discuss emerging molecular mechanisms underlying AHN that could be embraced in drug discovery to generate novel concepts and targets to treat diseases of ageing including neurodegeneration. To support this, we review cellular and molecular mechanisms that have recently been identified to assess how AHN is sustained throughout life and how AHN is associated with diseases. We also provide an outlook on strategies for developing correlated biomarkers that may accelerate the translation of pre-clinical and clinical data and review clinical trials for which modulation of AHN is part of the therapeutic strategy.

True alignment of preclinical and clinical research to enhance success in CNS drug development: a review of the current evidence.

Central nervous system pharmacological research and development has reached a critical turning point. Patients suffering from disorders afflicting the central nervous system are numerous and command significant attention from the pharmaceutical industry. However, given the numerous failures of promising drugs, many companies are no longer investing in or, indeed, are divesting from this therapeutic area. Central nervous system drug development must change in order to develop effective therapies to treat these patients. Preclinical research is a cornerstone of drug development; however, it is frequently criticised for its lack of predictive validity. Animal models and assays can be shown to be more predictive than reported and, on many occasions, the lack of thorough preclinical testing is potentially to blame for some of the clinical failures. Important factors such as translational aspects, nature of animal models, variances in acute versus chronic dosing, development of add-on therapies and understanding of the full dose-response relationship are too often neglected. Reducing the attrition rate in central nervous system drug development could be achieved by addressing these important questions before novel compounds enter the clinical phase. This review illustrates the relevance of employing these criteria to translational central nervous system research, better to ensure success in developing new drugs in this therapeutic area.

Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.

OBJECTIVE: To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs. DESIGN: Case-control study with replication. SETTING: Memory referral clinics in Canada and the United Kingdom. PARTICIPANTS: The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 nondemented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England. MAIN OUTCOME MEASURES: Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments. RESULTS: Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P< .05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2). CONCLUSIONS: Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.

Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families.

Mutations in the leucine-rich repeat kinase-2 gene (LRRK2) are responsible for some forms of familial as well as sporadic Parkinson's disease (PD). The purpose of this study was to examine the frequency of a single pathogenic mutation (6055G > A) in the kinase domain of this gene in United States and Tunisian familial PD and to compare clinical characteristics between patients with and without the mutation. Standardized case report forms were used for clinical and demographic data collection. We investigated the frequency of the most common substitution of LRRK2 (G2019S, 6055G>A) and its impact on epidemiological and phenotypic features. The frequency of mutations in Tunisian families was 42% (38/91) and in U.S. families 2.6% (1/39), with the unique opportunity to compare homozygous (n = 23) and heterozygous (n = 109) Tunisian carriers of G2019S substitutions. Individuals with G2019S substitutions had an older age at onset but few other differences compared with families negative for the substitution. Patients with LRRK2 mutations had typical clinical features of PD. Comparisons between individuals with heterozygous and homozygous LRRK2 mutations suggested that gene dosage was not correlated with phenotypic differences; however, the estimated penetrance was greater in homozygotes across all age groups.