Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid- (A)clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced A plaque load when given to APPswe/PS1⌬E9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects A plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain A plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of A pathology.
IntroductionAmyloid β (Aβ) accumulates in the extracellular space as diffuse and neuritic plaques in Alzheimer’s disease (AD). Aβ also deposits on the walls of arterioles as cerebral amyloid angiopathy (CAA) in most cases of AD and sometimes independently of AD. Apolipoprotein E (apoE) ɛ4 is associated with increases in both Aβ plaques and CAA in humans. Studies in mouse models that develop Aβ deposition have shown that murine apoE and human apoE4 have different abilities to facilitate plaque or CAA formation when studied independently. To better understand and compare the effects of murine apoE and human apoE4, we bred 5XFAD (line 7031) transgenic mice so that they expressed one copy of murine apoE and one copy of human apoE4 under the control of the normal murine apoE regulatory elements (5XFAD/apoEm/4). ResultsThe 5XFAD/apoEm/4 mice contained levels of parenchymal CAA that were intermediate between 5XFAD/apoEm/m and 5XFAD/apoE4/4 mice. In 5XFAD/apoEm/4 mice, we found that Aβ parenchymal plaques co-localized with much more apoE than did parenchymal CAA, suggesting differential co-aggregation of apoE with Aβ in plaques versus CAA. More importantly, within the brain parenchyma of the 5XFAD/apoEm/4 mice, plaques contained more murine apoE, which on its own results in more pronounced and earlier plaque formation, while CAA contained more human apoE4 which on its own results in more pronounced CAA formation. We further confirmed the co-aggregation of mouse apoE with Aβ in plaques by showing a strong correlation between insoluble mouse apoE and insoluble Aβ in PS1APP-21/apoEm/4 mice which develop plaques without CAA.ConclusionsThese studies suggest that both murine apoE and human apoE4 facilitate differential opposing effects in influencing Aβ plaques versus CAA via different co-aggregation with these two amyloid lesions and set the stage for understanding these effects at a molecular level.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0250-y) contains supplementary material, which is available to authorized users.
Background: This study was designed to estimate the costs of index hospitalizations after cardiac arrest in the United States. Methods and Results: We used the US Nationwide Inpatient Sample (2003–2012) to identify patients with cardiac arrest. Log transformation of inflation-adjusted cost was determined for care to patient outcomes. Overall, an estimated 1 387 396 patients were hospitalized after cardiac arrest. The mean age of the cohort was 66 years, 45% were women, and the majority were white. Inpatient procedures included coronary angiography (15%), percutaneous coronary intervention (7%), intra-aortic balloon pump (4.4%), therapeutic hypothermia (1.1%), and mechanical circulatory support (0.1%). The rates of therapeutic hypothermia increased from zero in 2003 to 2.7% in 2012 ( P <0.001). Both hospital charges and inflation-adjusted cost increased linearly over time. In a multivariate analysis, predictors of inflation-adjusted cost included large hospital size, urban teaching hospital, and length of stay. Among comorbidities, atrial fibrillation or fluid and electrolytes imbalance was most associated with cost. Among selected interventions, the cost was significantly increased with automatic implantable cardioverter defibrillators (odds ratio, 1.83; P <0.001), intra-aortic balloon pump (odds ratio, 1.50; P <0.001), hypothermia (odds ratio, 1.28; P <0.001), and extracorporeal membrane oxygenation (odds ratio, 2.38; P <0.001). Conclusions: In the period between 2003 and 2012, postcardiac arrest hospitalizations resulted in a steady rise in associated health care cost, likely related to increased length of stay, medical procedures, and systems of care. Although targeted cost containment for postarrest interventions may reduce the finance burden, there is an increasing need for funding research into prediction and prevention of cardiac arrest, which offers greater societal benefit.
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