Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer's disease

The epsilon4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4+ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whether APOE4 and TBI interact either through effects on amyloid-beta (Abeta) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3 (PDAPP:E3), human APOE4 (PDAPP:E4), or no APOE (PDAPP:E-/-). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. Abeta load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with Abeta-immunoreactive deposits (56% PDAPP:E4, 20% PDAPP:E3, 75% PDAPP:E-/-), but thioflavine-S-positive Abeta (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no Abeta deposition at this age. After TBI, all of the Abeta deposits present in PDAPP:E3 and PDAPP:E-/- mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:E-/- mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI via an effect on Abeta

Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis

SORLA is a sorting receptor that impairs processing of APP to soluble (s) APP and to Ass in cultured neurons, and that is poorly expressed in patients with Alzheimer's disease (AD). Here, we evaluated the consequences of Sorla gene defects on brain anatomy and function using mouse models of receptor deficiency. In line with a protective role for SORLA in APP metabolism, lack of the receptor results in increased amyloidogenic processing of endogenous APP, and in aggravated plaque deposition when introduced into PDAPP mice expressing mutant human APP. Surprisingly, increased levels of sAPP caused by receptor deficiency correlate with profound stimulation of neuronal ERK signaling and with enhanced neurogenesis, providing in vivo support for neurotrophic functions of sAPP. Our data document a role for SORLA not only in control of plaque burden but also in APP-dependent neuronal signaling, and suggest a molecular explanation for increased neurogenesis observed in some AD patients

Teaching animal science and genetics to Australian university undergraduates to enhance inquiry-based student learning and research with sheep: growth and conformation traits in crossbred prime lambs

The primary objective of this Australian Wool Education Trust funded teaching initiative on inquiry-based learning and research-led teaching approach was to enhance students' critical thinking and target their learning needs through active participation in hands-on experience with experimental sheep. The secondary objective was to study the effects of sire breed and sex on growth and body conformation traits in crossbred prime lambs at the University of Tasmania Farm, Cambridge. Body weight, average daily gain, body condition score, body length, withers height and chest girth in sixty first cross Merino lambs sired by White Suffolk and Poll Dorset rams were measured fortnightly over a ten-week period. Generalised linear model procedure in SAS was used for statistical analysis and included the fixed effects of sire breed, sex, fortnight and their second order interactions. Duncan's Multiple Range Test, correlations between growth and conformation traits and Bonferroni probabilities were estimated and used for comparisons.\ud \ud A fortnightly increase in lamb body weight, average daily gain and body condition score was evident. Wethers were heavier and had higher average daily gains than ewes. White Suffolk sired progeny had higher average daily gains than those sired by Dorset rams, but body weight did not differ between sire breeds. However, a highly significant interaction (P<0.0001) between sire breed and sex on body weight was evident as White Suffolk sired wethers were the heaviest prime lambs. It was concluded that the real world, hands-on research experience with experimental sheep, field trips, data collection, statistical analyses, data interpretation and seminar presentation of results facilitated a deeper student understanding of the scientific concepts of sire genetics and nutrition interactions in sheep growth

Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein

sorLA (sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid β-peptide (Aβ), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to A{beta}, whereas ablation of sorLA expression in knockout mice results in increased levels of Aβ in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into Aβ and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase Aβ production and plaque formation and promote spontaneous AD

Repertory grid technique as a group psychotherapy research instrument

This article provides a brief description of repertory grid technique and the measures which can be derived from it which may be of value to the investigator of group therapy. It reviews the technique's application in this area of research, with particular reference to studies of group therapy outcome, studies of the prediction of therapeutic change and studies of the group process.Peer reviewe