Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor TREM2 increase AD risk and activation of “disease-associated microglia” (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene expression changes associated with AD pathology and TREM2 in 5XFAD mice and human AD by snRNA-seq. We confirmed the presence of Trem2 -dependent DAM and identified a novel Serpina3n + C4b + reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less palpable in TREM2 R47H and R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

Ordered assembly of the tau protein into filaments characterizes multiple neurodegenerative diseases, which are called tauopathies. We previously reported that by electron cryo-microscopy (cryo-EM), tau filament structures from Alzheimer's disease (1,2), chronic traumatic encephalopathy (CTE) (3), Pick's disease (4) and corticobasal degeneration (CBD) (5) are distinct. Here we show that the structures of tau filaments from typical and atypical progressive supranuclear palsy (PSP), the most common tauopathy after Alzheimer's disease, define a previously unknown, three-layered fold. Moreover, the tau filament structures from globular glial tauopathy (GGT, Types I and II) are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs from the above and resembles the four-layered CBD fold. The majority of tau filaments from agingrelated tau astrogliopathy (ARTAG) also have the AGD fold. Surprisingly, tau protofilament structures from inherited cases with mutations +3/+16 in intron 10 of MAPT, the microtubule-associated protein tau gene, are identical to those from AGD, suggesting that a relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, tau filament structures from cases of familial British dementia (FBD) and familial Danish dementia (FDD) are the same as those from Alzheimer's disease and primary age-related tauopathy (PART). These structures provide the basis for a classification of tauopathies that also allows identification of new entities, as we show here for a case diagnosed as PSP, but with abundant spherical 4R tau inclusions in limbic and other brain areas. The structures of the tau fold of this new disease (Limbic-predominant Neuronal inclusion body 4R Tauopathy, LNT) were intermediate between those of GGT and PSP.

Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurologic disorder characterized by variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. By specifically searching published brain cDNA sequences for the presence of CAG repeats we identified unstable expansion of a CAG in a gene on chromosome 12 in all the 22 DRPLA patients examined. A good correlation between the size of the CAG repeat expansion and the ages of disease onset is found in this group. Patients with earlier onset tended to have a phenotype of progressive myoclonus epilepsy and larger expansions. We propose that the wide variety of clinical manifestations of DRPLA can now be explained by the variable unstable expansion of the CAG repeat.

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances ( 1 – 3 ). A higher frequency of the H1 haplotype of MAPT , the tau gene, is present in cases of CBD than in controls ( 4 , 5 ) and genome-wide association studies have identified additional risk factors ( 6 ). By histology, astrocytic plaques are diagnostic of CBD ( 7 , 8 ), as are detergent-insoluble tau fragments of 37 kDa by SDS-PAGE ( 9 ). Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD) ( 10 ), CBD is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R) ( 11 – 15 ). This distinguishes 4R tauopathies from Pick’s disease, filaments of which are made of three-repeat (3R) tau isoforms, and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE), where both 3R and 4R tau isoforms are found in the filaments ( 16 ). Here we report the structures of tau filaments extracted from the brains of three individuals with CBD using electron cryo-microscopy (cryo-EM). They were identical between cases, but distinct from those of Alzheimer’s disease, Pick’s disease and CTE ( 17 – 19 ). The core of CBD filaments comprises residues K274-E380 of tau, spanning the last residue of R1, the whole of R2, R3 and R4, as well as 12 amino acids after R4. It adopts a novel four-layered fold, which encloses a large non-proteinaceous density. The latter is surrounded by the side chains of lysine residues 290 and 294 from R2 and 370 from the sequence after R4. CBD is the first 4R tauopathy with filaments of known structure.

E.M. designed the study and wrote the initial draft of the manuscript. All authors collected samples and data, helped to interpret the results and reviewed drafts of the manuscript.Competing interests R.J.B. has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. R.J.B. receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with R.J.B., E.M. and N.R.B. as co-inventors, has submitted the US nonprovisional patent application 'Cerebrospinal fluid (CSF) tau rate of phosphorylation measurement to define stages of Alzheimer's disease and monitor brain kinases/phosphatases activity'. R.J.B. has received honoraria from Janssen and Pfizer as a speaker, and from Merck and Pfizer as an advisory board member. E.M. has received royalty payments for an educational program supported by Eli Lilly and as a member of a scientific advisory board for Eli Lilly.