The 18 kDa translocator protein (TSPO) is a widely used target for microglial PET imaging radioligands, but its expression in post-mortem normal and diseased human brain is not well described. We aimed at characterizing the TSPO expression in human control (CTRL) and Alzheimer's disease (AD) brains. Specifically, we sought to: (1) define the cell type(s) expressing TSPO; (2) compare tspo mRNA and TSPO levels between AD and CTRL brains; (3) correlate TSPO levels with quantitative neuropathological measures of reactive glia and AD neuropathological changes; and (4) investigate the effects of the TSPO rs6971 SNP on tspo mRNA and TSPO levels, glial responses and AD neuropathological changes. We performed quantitative immunohistochemistry and Western blot in post-mortem brain samples from CTRL and AD subjects, as well as analysis of publicly available mouse and human brain RNA-Seq datasets. We found that: (1) TSPO is expressed not just in microglia, but also in astrocytes, endothelial cells and vascular smooth muscle cells; (2) there is substantial overlap of tspo mRNA and TSPO levels between AD and CTRL subjects and in TSPO levels between temporal neocortex and white matter in both groups; (3) TSPO cortical burden does not correlate with the burden of activated microglia or reactive astrocytes, Aβ plaques or neurofibrillary tangles, or the cortical thickness; (4) the TSPO rs6971 SNP does not significantly impact tspo mRNA or TSPO levels, the magnitude of glial responses, the cortical thickness, or the burden of AD neuropathological changes. These results could inform ongoing efforts toward the development of reactive glia-specific PET radioligands.

The accumulation of neurofibrillary tangles in Alzheimer’s disease (AD) propagates with characteristic spatiotemporal patterns which follow brain network connections, implying trans-synaptic transmission of tauopathy. Since misfolded tau has been shown to transmit across synapses in AD animal models, we hypothesized that synapses in AD patients may contain misfolded tau. By immunofluorescence imaging of bipartite synapses from AD subjects, we detected tau protein in 38.4% of presynaptic and 50.9% of postsynaptic terminals. The pre/post distribution for hyperphosphorylated tau was 26.9%/30.7%, and for misfolded tau 18.3%/19.3%. In the temporal cortex, microscopic aggregates of tau, containing ultra-stable oligomers, were estimated to accumulate within trillions of synapses, outnumbering macroscopic tau aggregates such as tangles by 10000 fold. Non-demented elderly also showed considerable synaptic tau hyperphosphorylation and some misfolding, implicating the synapse as one of the first subcellular compartments affected by tauopathy. Misfolding of tau protein appeared to occur in situ inside synaptic terminals, without mislocalizing or mistrafficking. Misfolded tau at synapses may represent early signs of neuronal degeneration, mediators of synaptotoxicity, and anatomical substrates for transmitting tauopathy, but its actual role in these processes remain to be elucidated.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0146-2) contains supplementary material, which is available to authorized users.

Increasing evidence implicates the decline of microglial defensive responses in the progression of Alzheimer's disease (AD). Loss of function of genetic non-modifiable AD risk factors, as the triggering receptor expressed on myeloid cells 2 (TREM2) and the apolipoprotein E (APOE), associates with microglial dysfunction characterized by reduced clustering and survival around Aß plaques. However, the contribution of modifiable AD risk factors to microglial dysfunction is not known. We show here the concomitant activation of the HIF1-mediated stress response pathway and the transcription of aerobic respiration-related genes in Aß plaque-associated microglia (AßAM). We also demonstrate that AßAM mitochondria are elongated, a cellular response found in cells that maintain aerobic respiration under low nutrient and oxygen conditions, suggesting that HIF1 activation may be hijacking microglial mitochondrial metabolism.Overactivation of HIF1 induces microglial quiescence in cellulo, characterized by lower mitochondrial respiration and reduced proliferation. In vivo, overstabilization of HIF1, either genetically (von Hippel-Lindau deficient microglia) or by exposure to systemic hypoxia (mimicking vascular contributions to AD), reduces AßAM clustering and proliferation. We also observed increased Aß neuropathology in an AD mouse model exposed to hypoxia that mimics the loss of function of genetic AD risk genes. In the AD hippocampus, the upregulation of HIF1a and HIF1 target genes correlates with the presence of "nude" plaques (i.e., with reduced microglial coverage) in a hypoxia-prone brain area and the increase of Aß plaque-associated dystrophic neurites. Thus, low oxygen levels, a modifiable AD risk factor, disrupt microglial mitochondrial metabolism and converge with genetic susceptibility to cause AD microglial dysfunction.