Stage-specific functions of Semaphorin7A during adult hippocampal neurogenesis rely on distinct receptors

The guidance protein Semaphorin7A (Sema7A) is required for the proper development of the immune and nervous systems. Despite strong expression in the mature brain, the role of Sema7A in the adult remains poorly defined. Here we show that Sema7A utilizes different cell surface receptors to control the proliferation and differentiation of neural progenitors in the adult hippocampal dentate gyrus (DG), one of the select regions of the mature brain where neurogenesis occurs. PlexinC1 is selectively expressed in early neural progenitors in the adult mouse DG and mediates the inhibitory effects of Sema7A on progenitor proliferation. Subsequently, during differentiation of adult-born DG granule cells, Sema7A promotes dendrite growth, complexity and spine development through β1-subunit-containing integrin receptors. Our data identify Sema7A as a key regulator of adult hippocampal neurogenesis, providing an example of how differential receptor usage spatiotemporally controls and diversifies the effects of guidance cues in the adult brain

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimers Disease

The genetic component of Alzheimer’s disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage analysis. Next to known genes TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Next to these genes, the rare variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential driver genes in AD-GWAS loci. Rare damaging variants in these genes, and in particular loss-of-function variants, have a large effect on AD-risk, and they are enriched in early onset AD cases. The newly identified AD-associated genes provide additional evidence for a major role for APP-processing, Aβ-aggregation, lipid metabolism and microglial function in AD

A systematic review of depressed mood and anxiety by SES in youth aged 10-15 years

OBJECTIVES: A majority of population-based studies suggest prevalence of depressed mood and anxiety is most common during late adolescence to early adulthood. Mental health status has been linked previously to socio-economic status in adults. The purpose of this systematic literature review is to clarify if socio-economic status (SES) is a risk indicator of depressed mood or anxiety in youth between the ages of 10 to 15 years old. METHODS: We performed a systematic literature review to identify published or unpublished papers between January 1, 1980 and October 31, 2006 that reviewed depressed mood or anxiety by SES in youth aged 10-15 years. SYNTHESIS: We found nine studies that fulfilled our inclusion criteria and passed the methodological quality review. The prevalence of depressed mood or anxiety was 2.49 times higher (95% CI 2.33-2.67) in youth with low SES in comparison to youth with higher SES. DISCUSSION: The evidence suggests that low SES has an inverse association with the prevalence of depressed mood and anxiety in youth between the ages of 10 to 15 years old. Higher rates of depressed mood and anxiety among lower socio-economic status youth may impact emotional development and limit future educational and occupational achievement. CONCLUSION: Lower socio-economic status is associated with higher rates of depressed mood and anxiety in yout

A meta-analysis of marijuana and alcohol use by socio-economic status in adolescents aged 10-15 years

OBJECTIVES: A majority of population-based studies suggest prevalence of drug and alcohol risk behaviour increases during late adolescence to early adulthood. The purpose of this systematic literature review is to clarify if socio-economic status (SES) is a determinant of marijuana and alcohol risk behaviour in adolescents between the ages of 10-15 years. METHODS: We performed a meta-analysis to identify published or unpublished papers between January 1, 1980 and February 9, 2007 that reviewed marijuana and alcohol risk behaviour by SES in adolescents aged 10-15 years. SYNTHESIS: We found nine studies that fulfilled our inclusion criteria and passed the methodological quality review. The prevalence of marijuana and alcohol risk behaviour was 22% higher (RR = 1.22; 95% CI 1.14-1.31) in adolescents with low SES in comparison to adolescents with higher SES. Stratification by country of origin revealed that American and New Zealand studies had statistically significant variability in the reported effects as compared to European and UK studies. DISCUSSION: The evidence suggests that low SES has an inverse association with the prevalence of marijuana and alcohol risk behaviour in adolescents between the ages of 10-15 years. Higher rates of marijuana and alcohol risk behaviour among lower SES adolescents may impact emotional development, limit future educational and occupational achievement, and increase the likelihood for adult marijuana and alcohol addiction. CONCLUSION: Lower SES adolescents have higher rates of marijuana and alcohol risk behaviour than higher SES adolescent

Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease

Background: Survival after dementia diagnosis varies considerably. Previous studies were focused mainly on factors related to demographics and comorbidity rather than on Alzheimer's disease (AD)-related determinants. We set out to answer the question whether markers with proven diagnostic value also have prognostic value. We aimed to identify disease-related determinants associated with mortality in patients with AD. Methods: We included 616 patients (50% female; age 67 ± 8 years; mean Mini Mental State Examination score 22 ± 3) with dementia due to AD from the Amsterdam Dementia Cohort. Information on mortality was obtained from the Dutch Municipal Register. We used age- and sex-adjusted Cox proportional hazards analysis to study associations of baseline demographics, comorbidity, neuropsychology, magnetic resonance imaging (MRI) (medial temporal lobe, global cortical and parietal atrophy, and measures of small vessel disease), and cerebrospinal fluid (CSF) (β-amyloid 1-42, total tau, and tau phosphorylated at threonine 181 [p-tau]) with mortality (outcome). In addition, we built a multivariate model using forward selection. Results: After an average of 4.9 ± 2.0 years, 213 (35%) patients had died. Age- and sex-adjusted Cox models showed that older age (HR 1.29 [95% CI 1.12-1.48]), male sex (HR 1.60 [95% CI 1.22-2.11]), worse scores on cognitive functioning (HR 1.14 [95% CI 1.01-1.30] to 1.31 [95% CI 1.13-1.52]), and more global and hippocampal atrophy on MRI (HR 1.18 [95% CI 1.01-1.37] and HR 1.18 [95% CI 1.02-1.37]) were associated with increased risk of mortality. There were no associations with comorbidity, level of activities of daily living, apolipoprotein E (APOE) ϵ4 status, or duration of disease. Using forward selection, the multivariate model included a panel of age, sex, cognitive tests, atrophy of the medial temporal lobe, and CSF p-tau. Conclusions: In this relatively young sample of patients with AD, disease-related determinants were associated with an increased risk of mortality, whereas neither comorbidity nor APOE genotype had any prognostic value

Stage-specific functions of Semaphorin7A during adult hippocampal neurogenesis rely on distinct receptors

The guidance protein Semaphorin7A (Sema7A) is required for the proper development of the immune and nervous systems. Despite strong expression in the mature brain, the role of Sema7A in the adult remains poorly defined. Here we show that Sema7A utilizes different cell surface receptors to control the proliferation and differentiation of neural progenitors in the adult hippocampal dentate gyrus (DG), one of the select regions of the mature brain where neurogenesis occurs. PlexinC1 is selectively expressed in early neural progenitors in the adult mouse DG and mediates the inhibitory effects of Sema7A on progenitor proliferation. Subsequently, during differentiation of adult-born DG granule cells, Sema7A promotes dendrite growth, complexity and spine development through β1-subunit-containing integrin receptors. Our data identify Sema7A as a key regulator of adult hippocampal neurogenesis, providing an example of how differential receptor usage spatiotemporally controls and diversifies the effects of guidance cues in the adult brain