Accumulation of pathological tau protein is a major hallmark of Alzheimer’s disease. Tau protein spreads from the entorhinal cortex to the hippocampal region early in the disease. Microglia, the primary phagocytes in the brain, are positively correlated with tau pathology, but their involvement in tau propagation is unknown. We developed an adeno-associated virus–based model exhibiting rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. We found that depleting microglia dramatically suppressed the propagation of tau and reduced excitability in the dentate gyrus in this mouse model. Moreover, we demonstrate that microglia spread tau via exosome secretion, and inhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo. These data suggest that microglia and exosomes contribute to the progression of tauopathy and that the exosome secretion pathway may be a therapeutic target.

SUMMARY Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S tau mice. Reducing TIA1 decreases the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibits the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles (NFTs). Despite the increase in NFTs, TIA1 reduction increases neuronal survival and rescues behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity, and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a paradigm in which dysfunction of the translational stress response leads to tau-mediated pathology.

Which principles determine the organization of the intricate network formed by nerve fibers that link the primate cerebral cortex? We addressed this issue for the connections of primate visual cortices by systematically analyzing how the existence or absence of connections, their density as well as laminar patterns of projection origins and terminations are correlated with distance, similarity in cortical type as well as neuronal density or laminar thickness of cortical areas. Analyses were based on four extensive compilations of qualitative as well as quantitative data for connections of the primate visual cortical system in macaque monkeys (Felleman and Van Essen, 1991; Barbas, 1986; Barbas and Rempel-Clower, 1997; Barone et al., 2000; Markov et al., 2014). Distance and thickness similarity were not consistently correlated with connection features, but similarity of cortical type, determined by qualitative features of laminar differentiation, or measured quantitatively as the areas' overall neuronal density, was a reliable predictor for the existence of connections between areas. Cortical type similarity was also consistently and closely correlated with characteristic laminar connection profiles: structurally dissimilar areas had origin and termination patterns that were biased to the upper or deep cortical layers, while similar areas showed more bilaminar origins and terminations. These results suggest that patterns of corticocortical connections of primate visual cortices are closely linked to the stratified architecture of the cerebral cortex. In particular, the regularity of laminar projection origins and terminations arises from the structural differences between cortical areas. The observed integration of projections with the intrinsic cortical architecture provides a structural basis for advanced theories of cortical organization and function.

A principal challenge of systems neuroscience is to understand the unique characteristics of cortical neurons and circuits that enable area- and species-specific sensory encoding, motor function, cognition, and behavior. To address this issue, we compared properties of layer 3 pyramidal neurons in 2 cortical areas that span a broad range of cortical function-primary sensory (V1), to cognitive (frontal)-in the mouse and the rhesus monkey. Hierarchical clustering and discriminant analyses of 15 physiological and 25 morphological variables revealed 2 fundamental principles. First, V1 and frontal neurons are remarkably similar with regard to nearly every property in the mouse, while the opposite is true in the monkey, with V1 and frontal neurons exhibiting significant differences in nearly every property assessed. Second, neurons within visual and frontal areas differ significantly between the mouse and the monkey. Neurons in mouse and monkey V1 are the same size, but differ in nearly every other way; mouse frontal cortical neurons are smaller than those in the monkey and also differ substantially with regard to most other properties. These findings have broad implications for understanding the differential contributions of heterogeneous neuronal types in construction of cortical microcircuitry in diverse brain areas and species.

Summary The primate dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) focus attention on relevant signals and suppress noise in cognitive tasks. However, their synaptic interactions and unique roles in cognitive control are unknown. We report that two distinct pathways to DLPFC area 9, one from the neighboring area 46 and the other from the functionally distinct ACC, similarly innervate excitatory neurons associated with selecting relevant stimuli. However, ACC has more prevalent and larger synapses with inhibitory neurons and preferentially innervates calbindin inhibitory neurons, which reduce noise by inhibiting excitatory neurons. In contrast, area 46 mostly innervates calretinin inhibitory neurons, which disinhibit excitatory neurons. These synaptic specializations suggest that ACC has a greater impact in reducing noise in dorsolateral areas during challenging cognitive tasks involving conflict, error, or reversing decisions, mechanisms that are disrupted in schizophrenia. These observations highlight the unique roles of the DLPFC and ACC in cognitive control.