The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease

BACKGROUND: The R47H variant of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) confers greatly increased risk for Alzheimer's disease (AD), reflective of a central role for myeloid cells in neurodegeneration. Understanding how this variant confers AD risk promises to provide important insights into how myeloid cells contribute to AD pathogenesis and progression. METHODS: In order to investigate this mechanism, CRISPR/Cas9 was used to generate a mouse model of AD harboring one copy of the single nucleotide polymorphism (SNP) encoding the R47H variant in murine Trem2. TREM2 expression, myeloid cell responses to amyloid deposition, plaque burden, and neuritic dystrophy were assessed at 4 months of age. RESULTS: AD mice heterozygous for the Trem2 R47H allele exhibited reduced total Trem2 mRNA expression, reduced TREM2 expression around plaques, and reduced association of myeloid cells with plaques. These results were comparable to AD mice lacking one copy of Trem2. AD mice heterozygous for the Trem2 R47H allele also showed reduced myeloid cell responses to amyloid deposition, including a reduction in proliferation and a reduction in CD45 expression around plaques. Expression of the Trem2 R47H variant also reduced dense core plaque number but increased plaque-associated neuritic dystrophy. CONCLUSIONS: These data suggest that the AD-associated TREM2 R47H variant increases risk for AD by conferring a loss of TREM2 function and enhancing neuritic dystrophy around plaques

Natural atmospheric deposition of molybdenum: a global model and implications for tropical forests

Abstract Molybdenum (Mo) is an essential trace metal that plays a central role in biological nitrogen fixation (BNF) as the cofactor in the conventional form of the nitrogenase enzyme. The low availability of Mo in soils often constrains BNF in many terrestrial ecosystems. Atmospheric sources may supply a critical source of exogenous Mo to regions with highly weathered soils likely low in Mo, particularly in tropical forests where BNF is thought to be high. Here, we present results of a global model of Mo deposition that considers the principal natural sources of atmospheric Mo—windborne mineral dust, sea-salt aerosols, and volcanic sources—which operate over geologic time. The largest source of mineral dust globally is from North Africa. We quantified Mo concentrations in dust and sediments from the Bodélé Depression, a large source within North Africa, to constrain our model. Because the Mo concentration of seawater is relatively high for a trace element, we also hypothesized that sea-salt aerosols would contribute atmospheric Mo. Our model predicts higher Mo deposition to terrestrial ecosystems along coasts downstream in trade winds, near active volcanoes, and in areas that receive dust deposition from North Africa, such as the northern Amazon Basin, the Caribbean, and Central America. Regions with higher Mo deposition tend to be areas where BNF has previously been measured. The lowest Mo deposition occurs in the high latitudes, northern parts of North America, Western Australia, Southern Africa, and much of central South America. Atmospheric transport of Mo likely plays an important role in supplying Mo to ecosystems across geologic time, particularly in regions with highly weathered soils