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APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE4 increases brain amyloid-β (Aβ) pathology relative to other ApoE isoforms1. However, whether APOE independently influences tau pathology, the other major proteinopathy of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knockin (KI) or ApoE knockout (KO) background, we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by 3 months of age compared to P301S/E2, P301S/E3 and P301S/EKO mice. By 9 months of age, P301S mice with different ApoE genotypes display distinct p-tau staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity following LPS treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of TNFα secretion and markedly reduced neuronal viability compared to neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNFα. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared to the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In Aβ-pathology positive individuals with symptomatic AD who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independent of Aβ pathology. ApoE4 exerts a “toxic” gain of function whereas the absence of ApoE is protective.

The National Alzheimer's Coordinating Center (NACC) is responsible for developing and maintaining a database of participant information collected from the 29 Alzheimer's Disease Centers (ADCs) funded by the National Institute on Aging (NIA). The NIA appointed the ADC Clinical Task Force to determine and define an expanded, standardized clinical data set, called the Uniform Data Set (UDS). The goal of the UDS is to provide ADC researchers a standard set of assessment procedures, collected longitudinally, to better characterize ADC participants with mild Alzheimer disease and mild cognitive impairment in comparison with nondemented controls. NACC implemented the UDS (September 2005) by developing data collection forms for initial and follow-up visits based on Clinical Task Force definitions, a relational database, and a data submission system accessible by all ADCs. The NIA requires ADCs to submit UDS data to NACC for all their Clinical Core participants. Thus, the NACC web site (https://www.alz.washington.edu) was enhanced to provide efficient and secure access data submission and retrieval systems.

Purpose Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. Patients and Methods We performed a first in-human trial of Escherichia coli–produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Results Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. Conclusion IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.

Article abstract-The expression levels of three synaptic proteins (synaptophysin, synaptotagmin,) in AD cases clinically classified by Clinical Dementia Rating (CDR) score were analyzed. Compared with control subjects (CDR ϭ 0), mild (early) AD (CDR ϭ 0.5 to 1) cases had a 25% loss of synaptophysin immunoreactivity. Levels of synaptotagmin and GAP43 were unchanged in mild AD, but cases with CDR of Ͼ1 had a progressive decrement in these synaptic proteins. Thus, synaptic injury in frontal cortex is an early event in AD. The cognitive alterations in patients with AD are closely associated with synaptic loss 1 and neurofibrillary pathology 2 in the limbic system and neocortex. Understanding of the time course of and relationship between neuropathologic and behavioral alteration in AD has been greatly enhanced in recent years by the development of more sensitive neuropsychologic and neuroanatomic tools that can detect subtle cognitive and structural alterations in patients with early AD. Among them, the Clinical Dementia Rating (CDR) scoring system and the Braak staging system 3 have been especially useful. Based on these criteria, some studies have proposed that diffuse amyloid deposits might contribute to neurodegeneration in early stages of the disease, 4 and others have suggested that synaptic and neurofibrillary pathology might be an early/earlier event preceding extracellular amyloid deposition.5 This indicates that alterations in synaptic functioning might occur early in AD and that molecular biomarkers of active synapses, such as synaptotagmin (p65), 6 could be good indicators of early synaptic damage. Synaptotagmin is a 65-kd calcium sensor protein found in the synaptic vesicles that is modulated during synaptic activation. The hypothesis is that changes in synaptotagmin might be the most sensitive indicator of synaptic changes in mild (early) AD. In this context, the main objective of the present study was to analyze expression levels of three synaptic proteins, namely, synaptophysin (general synaptic marker), synaptotagmin (marker of synaptic activity), 7 and growth-associated protein 43 (GAP43; marker of synaptic sprouting) in the brains of patients with mild (early), moderate, and severe AD. Materials and methods.This study was performed with autopsy material from 42 patients (table) studied neurologically and psychometrically during life at the AD Research Center/University of California, San Diego, and at the Washington University School of Medicine, St. Louis, MO. The CDR score was assigned during life following previously published criteria; this scoring has demonstrated interrater reliability.8 Furthermore, to assess the cognitive status just before death, a retrospective CDR score was assigned based on family interviews. Therefore, the CDR score reflects cognitive status right before death. The CDR scale ranged from 0 to 3 (0, 0.5, 1, 2, and 3). Paraffin sections from 4% buffered formalin-fixed neocortical, limbic system, and subcortical material were used for routine neuropathologic examination a...