Faculty Bibliography

Background: We have previously demonstrated that anti-beta-sheet conformational monoclonal antibodies (mAbs) recognize pathological oligomeric forms of Abeta and Tau in tissue samples of human Alzheimer's Disease (AD) brains and in AD mouse models (Goni et al 2015, Alzheimer & Dementia pp 845-6). We have now tested one of our mAbs in aged 3xTg AD animals with extensive preexisting Abeta and Tau related pathology with weekly injections of the TABP1 mAb. Methods: Two groups of 16 months old 3xTg AD animals were inoculated i.p. biweekly for three weeks and weekly thereafter for 5 weeks with either 100 mug of TABP1 in 100 muL of sterile saline or with 100 muL of vehicle alone. Radial Arm Maze behavioral analysis was performed after the treatment, followed by sacrifice and harvesting of the brains for immuno-histochemical and biochemical analyses. Results: No adverse reactions were demonstrated during the treatment. The TABP1 infused animals showed significant cognitive rescue compared to the controls. No significant differences were noted with the immunohistochemical quantitation of amyloid plaques or tau pathology; although there was a trend for reduced deposition in the infused animals. However, there was a significant decrease of the soluble and oligomeric Abeta (mainly Abeta1-42) and pathological Tau in the infused animals versus the controls. Conclusions: Anti-conformational monoclonal antibodies infused i.p. can ameliorate behavioral deficits in AD model mice. The mechanism is likely related to reductions of the levels of soluble oligomeric forms of Abeta and Tau; these species have been most closely linked to the cognitive deficits in AD patients. The results are encouraging for the further testing of humanized versions of these mAbs in clinical trials

Background: Numerous studies have linked depressive symptoms, or syndromal depression, to increased risk for Alzheimer's disease (AD) irrespective of its onset age. The neurobiological basis for this association, however, remains poorly understood. Studies which have examined biomarkers of AD in peripheral and central tissues in depression, including CSF Abeta42 (Abeta42) and brain amyloid using PET ligands, have provided conflicting results. These discrepant results may have been due to methodological differences across studies, including heterogeneity in study populations (e.g., inclusion of individuals with mild cognitive impairment) and the use of approaches for detecting depression (e.g., patients' self-ratings) that lack diagnostic specificity. In addition, only a few studies have employed structured interviews based on DSM diagnostic criteria or standardized pre-analytical and laboratory procedures for quantifying Abeta. Finally, all of the existing studies have been limited to cross sectional comparisons based on a single Abeta determination; thus, it is not known if these abnormalities persist over time and if depressive symptoms influence Abeta levels. The current study was conducted to address the aforementioned limitations. Methods: Our baseline sample consisted of 47 subjects aged 60 years and older; 28 with LMDD and 19 controls. Of the 47 older subjects, 31 were e4 non-carriers and 16 were e4 carriers. All subjects were cognitively-intact and had a) no evidence of dementia, b) a Mini-Mental State Exam score of at least 28, and c) no gross MRI abnormalities other than white matter hyperintensities. CSF collection was repeated after 3 years for 36 of these individuals: 19 with LLMD and 17 controls. We evaluated the effects of diagnosis and time on Abeta42 levels with 2 x 2 repeated measures ANOVA. Results: Longitudinal comparisons of controls and LLMD revealed that the LLMD group was significantly less depressed at follow up than at baseline, as determined by the HAM-D, whereas controls remained unchanged. There was a significant interaction between diagnosis and time on CSF Abeta42 levels. Importantly, the reductions in depressive symptoms observed over time were significantly correlated with increases in CSF Abeta42 levels, both in the entire cohort (r =-.451, p =.006) and within the LLMD group (r =-.547, p =.015), but not in the control group (p =.809). The same relationship was not significant with Abeta40 (Pomara et al., 2016). Performance on cognitive indices remained unchanged and was not significantly correlated with changes in AD Biomarkers. Conclusions: Cognitively-intact, elderly individuals with LLMD, who were more depressed at baseline, but less depressed at the 3 year follow-up, showed both a reduction in baseline CSF Abeta42 (Pomara et al., 2012) and elevation in Abeta42 at 3 year follow-up. In addition, changes in CSF Abeta42 were correlated with changes in depressive symptoms. Future studies should determine if these state-dependent changes in Abeta42 mediate the increased risk of AD contributed by LLMD. If this is the case, the need for more aggressive treatment of LLMD cannot be underestimated

Alzheimer disease (AD) represents one of the greatest medical challenges of this century; the condition is becoming increasingly prevalent worldwide and no effective treatments have been developed for this terminal disease. Because the disease manifests at a late stage after a long period of clinically silent neurodegeneration, knowledge of the modifiable risk factors and the implementation of biomarkers is crucial in the primary prevention of the disease and presymptomatic detection of AD, respectively. This article discusses the growing epidemic of AD and antecedent risk factors in the disease process. Disease biomarkers are discussed, and the implications that this may have for the treatment of this currently incurable disease.

Depression has been linked to Alzheimer's disease as either an increased risk factor for its development or as a prodromal symptom. The neurobiological basis for such an association, however, remains poorly understood. Numerous studies have examined whether changes in amyloid beta (Abeta) metabolism, which are implicated in the pathogenesis of Alzheimer's disease, are also found in depression. In this paper, we investigated the relationship between depressive symptoms and cerebrospinal fluid (CSF) Abeta indices in otherwise healthy, cognitively normal elderly with late-life major depression (LLMD) and controls using a longitudinal approach, which is a novel contribution toward the literature. Significantly lower levels of CSF Abeta42 were observed in the LLMD group at baseline and were associated with more severe depressive symptoms. During longitudinal follow-up, the depressed group remained cognitively unchanged, but was significantly less depressed than at baseline. A greater improvement in depressive symptoms was associated with increases in CSF Abeta42 levels in both groups. Increases in CSF Abeta42 and Abeta40 were also associated with increased CSF total-tau levels. Our results suggest that LLMD may be associated with state-dependent effects of CSF Abeta42 levels. Future studies should determine whether the association reflects state-dependent changes in neuronal activity and/or brain amyloid burden in depression.

Because of an extra copy of the Abeta precursor protein gene on chromosome 21, Down syndrome (DS) individuals develop high levels of Abeta peptides and Alzheimer disease-like brain amyloidosis early in life. Here we show that the gamma-secretase activating protein (GSAP), a key enzyme in amyloidogenesis, is increased in DS brains and specifically regulated at the transcriptional level by GATA1 transcription factor. The discovery of this novel pathway has translational implications for DS, because pharmacological inhibition of GSAP is an attractive and viable Abeta-lowering therapeutic strategy for this disorder. ANN NEUROL 2016;79:138-143.