A novel reciprocal and biphasic relationship between membrane cholesterol and beta-secretase activity in SH-SY5Y cells and in human platelets.

Research into the cause of Alzheimer's disease (AD) has identified strong connections to cholesterol. Cholesterol and cholesterol esters can modulate amyloid precursor protein (APP) processing, thus altering production of the A beta peptides that deposit in cortical amyloid plaques. Processing depends on the encounter between APP and cellular secretases, and is thus subject to the influence of cholesterol-dependent factors including protein trafficking, and distribution between membrane subdomains. We have directly investigated endogenous membrane beta-secretase activity in the presence of a range of membrane cholesterol levels in SH-SY5Y human neuroblastoma cells and human platelets. Membrane cholesterol significantly influenced membrane beta-secretase activity in a biphasic manner, with positive correlations at higher membrane cholesterol levels, and negative correlations at lower membrane cholesterol levels. Platelets from individuals with AD or mild cognitive impairment (n = 172) were significantly more likely to lie within the negative correlation zone than control platelets (n = 171). Pharmacological inhibition of SH-SY5Y beta-secretase activity resulted in increased membrane cholesterol levels. Our findings are consistent with the existence of a homeostatic feedback loop between membrane cholesterol level and membrane beta-secretase activity, and suggest that this regulatory mechanism is disrupted in platelets from individuals with cognitive impairment.

Alpha7 nicotinic acetylcholine receptor gene and reduced risk of Alzheimer's disease.

Background: Sporadic Alzheimer's disease (AD) is a common disabling disease of complex aetiology for which there are limited therapeutic options. We sought to investigate the role of the alpha 7 nicotinic acetylcholine receptor gene (CHRNA7) in influencing risk of AD in a large population. CHRNA7 is a strong candidate gene for AD for several reasons: (1) its expression is altered differentially in the AD brain; (2) it interacts directly with beta amyloid peptide (A beta(42)); and (3) agonist activation induces several neuroprotective pathways.

Variation in RTN3 and PPIL2 Genes Does not Influence Platelet Membrane β-Secretase Activity or Susceptibility to Alzheimer’s Disease in the Northern Irish Population

beta-site amyloid precursor protein cleaving enzyme (BACE1) is the rate-limiting enzyme for production of beta-amyloid peptides (A beta), which are proposed to drive the pathological changes found in Alzheimer's disease (AD). Reticulon 3 (RTN3) is a negative modulator of BACE1 (beta-secretase) proteolytic activity, while peptidylprolyl isomerase (cyclophilin)-like 2 (PPIL2) positively regulates BACE1 expression. The present study investigated whether there was any association between genetic variation in RTN3 and PPIL2, and either risk for AD, or levels of platelet beta-secretase activity, in a large Northern Irish case-control sample. Four hundred and sixty-nine patients with a diagnosis of probable AD (NINCDS-ADRDA criteria) and 347 control individuals (MMSE > 28/30) were genotyped. SNPs in both genes were selected by downloading genotype data from the International HapMap Project (Phase II) and tags selected using multimarker approach in Haploview, where r (2) > 0.8 and LOD > 3.0. Non-synonymous SNPs of interest were also included. Genotyping was performed by Sequenom iPLEX and TaqMan technologies. Alleles, genotypes and multi-marker haplotypes were tested for association with AD, and platelet beta-secretase activities were measured for a subset of individuals (n = 231). Eight SNPs in RTN3 and 7 in PPIL2 were genotyped. We found no significant associations between allele, genotype or haplotype frequencies and risk of AD. Further, there was no effect of genotype on platelet membrane beta-secretase activity. We conclude that common or potentially functional genetic variation in these BACE1 interacting proteins does not affect platelet membrane beta-secretase activity or contribute to risk of AD in this population.

Crossing borders through cyberspace: a discussion of a social work education electronic exchange pilot project across the Atlantic

This article discusses a trial electronic exchange project developed between social work education departments in the Republic of Ireland and the USA. It outlines the contemporary significance and challenges of integrating global content into national social work curricula, which are often strongly tied to statutory or accreditation requirements. The mechanics of the exchange are explained and critiqued in detail. An illustrative example of how the transnational students discussed two questions is analyzed. The article finds that an international electronic exchange has great potential to make global social work real to students by allowing them to cross borders through cyberspace, however it requires careful planning and attention to cultural and educational system differences.

Peadiatric social admission

The phenomenon of paediatric social admission describes the hospitalisation of children for medicallynon- urgent and/or social reasons. Much of the research in this field has been in relation to avoidable admissions which have been identified, studied and condoned based on strict medical criteria. Such research has tended to mask the significance of social factors and the commonplace practice of Paediatric Social Admission. This paper examines decision making from the perspective of the health professionals at the clinical coal face. It explores how health professionals are influenced by social, organisational and subjective factors which determine their decision to admit or not to admit a child to hospital. The paper reports findings from interviews with 27 health professionals involved in PSA and a document audit of 21 specific cases. In doing so it begins to address the inherent paradox of responding to a child and families social needs in a medical context.

A case study in group learning and supervision

Student units or the group-based field education and supervision of social work students offer many advantages as an efficient field placement model as well as opportunities for students to learn from each other through sharing knowledge, working collaboratively, hearing different perspectives and discussing issues. Despite the enormous potential of student units, they are a largely uncharted territory. There is a scarcity of literature on the topic and very few guidelines as to the provision of student units. The term student unit covers a broad range of student group learning opportunities and activities. This study explores this model of social work field education and its implications for student field work learning in a group context. The discussion is based on a review of the experiences, opinions and impressions of participants of an actual university based social work student unit.

The paradox of peadiatric social admission

The paradox of paediatric social admission involves the hospitalisation of children for medically non- urgent and/or social reasons. Much of the research in this field has been in relation to avoidable admissions which have been identified, studied and condoned based on strict medical criteria. Such research has tended to mask the significance of social influences and the reasons why health professionals make such decisions. This paper explores social, organisational and subjective influences on medical decision making and is based on study involving interviews with 27 health professionals directly involved in paediatric social admissions (PSA). The findings highlight inherent paradoxes as a consequence of responding to social concerns in a medical context.

BACE1 mRNA Expression in Alzheimer's Disease Postmortem Brain Tissue

ß-site AßPP cleaving enzyme 1 (BACE1) catalyses the rate-limiting step for production of amyloid-ß (Aß) peptides, involved in the pathological cascade underlying Alzheimer's disease (AD). Elevated BACE1 protein levels and activity have been reported in AD postmortem brains. Our study explored whether this was due to elevated BACE1 mRNA expression. RNA was prepared from five brain regions in three study groups: controls, individuals with AD, and another neurodegenerative disease group affected by either Parkinson's disease (PD) or dementia with Lewy bodies (DLB). BACE1 mRNA levels were measured using quantitative realtime PCR (qPCR) and analyzed by qbasePLUS using validated stably-expressed reference genes. Expression of glial and neuronal markers (glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE), respectively) were also analyzed to quantify the changing activities of these cell populations in the tissue. BACE1 mRNA levels were significantly elevated in medial temporal and superior parietal gyri, compared to the PD/DLB and/or control groups. Superior frontal gryus BACE1 mRNA levels were significantly increased in the PD/DLB group, compared to AD and control groups. For the AD group, BACE1 mRNA changes were analyzed in the context of the reduced NSE mRNA, and strongly increased GFAP mRNA levels apparent as AD progressed (indicated by Braak stage). This analysis suggested that increased BACE1 mRNA expression in remaining neuronal cells may contribute to the increased BACE1 protein levels and activity found in brain regions affected by AD.