Citations

Abstract Background: The p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) has been reported to increase Alzheimer’s disease (AD) risk. This mutation in the extracellular domain of TREM2 localizes at the cleavage site and was shown to enhance shedding and impair phagocytosis in vitro by ectopic expression of TREM2-H157Y in HEK293 cells. However, the physiological and AD-related outcomes of TREM2 H157Y mutation in vivo remain unknown.Methods: We generated a novel Trem2 H157Y knock-in mouse model through CRISPR-Cas9 technology and investigated how Trem2 H157Y mutation impacts TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathology by conducting biochemical assays, immunofluorescent staining, hippocampal electrophysiology, and in vivo micro-dialysis in awake, free-moving animals.Results: Consistent with previous in vitro findings, TREM2-H157Y increases the amount of soluble TREM2 (sTREM2) in the cortex and serum of mutant mice compared to the wild type controls. Interestingly, the Trem2 H157Y variant enhances synaptic plasticity without affecting microglial density and morphology. In the presence of amyloid pathology, TREM2-H157Y surprisingly accelerates Aβ clearance and reduces amyloid burden and microgliosis. Conclusion: Taken together, our findings support a beneficial effect of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD, we speculate TREM2-H157Y might increase AD risk through an amyloid-independent pathway, as such its effects on tauopathy and neurodegeneration merit further investigation.

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.

Although the ε2 allele of apolipoprotein E ( APOE2 ) benefits longevity, its mechanism is not understood. The protective effects of the APOE 2 on Alzheimer’s disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound APOE2 effects on longevity. Herein, we showed that the association between APOE2 and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models. Notably, APOE2 was associated with preserved activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where APOE2 has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate that APOE2 can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of APOE2 -mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.

ABSTRACT The present investigation tested the hypotheses that there would be greater prevalence of expiratory flow limitation (EFL) in endurance-trained (ET) youth cyclists compared with a recreationally active control (CON) group. METHODS Twelve ET youth male cyclists (16.3 ± 1.0 yr (13–18 yr), 176.5 ± 6.2 cm, 64.2 ± 5.9 kg) and 12 CON subjects (17.6 ± 2.2 yr (13–18 yr), 177.9 ± 7.1 cm, 74.8 ± 11.2 kg) completed an incremental exercise test to determine peak oxygen consumption (V˙O 2peak ) on a cycle ergometer. Maximal flow volume loops (MFVL), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), FEV 1 /FVC, forced expiratory flow between 25% and 75% of FVC, and peak expiratory flow were assessed before and after exercise, with inspiratory capacity maneuvers and dyspnea ratings measured in the last 20 s of each stage. EFL was quantified as the percentage of the expiratory tidal volume that overlapped with the maximal flow volume loop. RESULTS V˙O 2peak , dyspnea ratings at peak, and ventilation were higher in the ET compared with CON group ( P < 0.05). The ET group experienced greater EFL prevalence at V˙O 2peak , with 11 of 12 subjects exhibiting EFL compared with 5 of 12 subjects in the CON group ( P = 0.014). When matched for absolute ventilation of 20, 40, 60, 80, and 100 L·min −1 , there were no differences in EFL severity between the ET and CON groups ( P = 0.473). CONCLUSIONS Elite youth male cyclists have a greater prevalence of EFL at maximal exercise than do CON subjects who are similar in age, height, and lung size. Future research should determine whether EFL in youth ET male cyclists may limit their exercise performance.

APOE4 exacerbates α-synuclein pathology in a synucleinopathy mouse model, and APOE4 genotype associates with increased α-synuclein pathology in humans.

How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606