Zinc finger proteins targeted to MAPT safely repress tau mRNA in the adult mouse brain and protect against Aβ toxicity.

In Alzheimer's disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded tau aggregates extracted from human AD brains drives templated spreading of tau pathology within WT mouse brain. Here, we assessed the impact of Aβ copathology, of deleting loci known to modify AD risk (Ptk2b, Grn, and Tmem106b) and of pharmacological intervention with an Fyn kinase inhibitor on tau spreading after injection of AD tau extracts. The density and spreading of tau inclusions triggered by human tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1ΔE9 transgenic and App^NL-F/NL-F knock-in mice. In mice with human tau sequence replacing mouse tau, template matching enhanced neuritic tau burden. Human AD brain tau-enriched preparations contained aggregated Aβ, and the Aβ coinjection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from tau accumulation and could be ameliorated by depleting Aβ from tau extracts. These data suggest that Aβ and tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer–induced signaling, or deleting expression of the progranulin and TMEM106B lysosomal proteins, did not alter the somatic tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic tau after injection of human AD tau seeds into WT mice. These studies refine our knowledge of factors capable of modulating tau spreading.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease marked by progressive motor deficits and Purkinje cell (PC) degeneration, driven by polyglutamine expansion in ataxin-1. While oligodendroglial dysfunction precedes PC loss, its direct contribution toward SCA1 pathogenesis remains unclear. Here, using an oligodendroglia-specific SCA1 conditional knockin mouse model, we demonstrate that mutant ataxin-1 in oligodendrocytes is sufficient to drive aspects of SCA1-related pathology, including dysregulated myelination, PC axonal shrinkage, and torpedo formation, ultimately impairing motor coordination. Transcriptomic analysis uncovers cerebellar oligodendrocyte subtypes with distinct gene expression signatures and aberrant abundance that contribute to demyelination. This, compounded by a progressive decline in the neuroprotective functions of a cerebellum-specific oligodendrocyte subtype, establishes a critical link between demyelination, axo-myelinic dysfunction, and axonal pathology in SCA1. Upstream transcriptional regulator analysis in oligodendroglia identifies transcription factor 7-like 2 (TCF7L2) and huntingtin (HTT) as key mediators of oligodendroglial dysfunction in SCA1, suggesting shared pathogenic mechanisms with other polyglutamine diseases. Collectively, these findings establish oligodendroglia as key mediators of SCA1 pathogenesis and underscore their critical role in preserving PC axonal integrity.

More than 30 years after the discovery of the genetic cause of spinocerebellar ataxia type 1 (SCA1), selective Purkinje cell vulnerability remains a defining feature of disease pathogenesis. Increasing evidence also implicates glial cells, including oligodendroglia, astroglia, and microglia, as important contributors to neurodegeneration in SCA1 and other ataxias. In this review, we summarize current evidence for the mechanisms through which glia contribute to SCA1 progression and pathology. Early oligodendroglial dys-function leads to cell-autonomous myelination deficits and non-cell-autonomous im-pairments in Purkinje cell axonal health. Astroglial dysfunction, particularly in Berg-mann glia, disrupts glutamate homeostasis and is associated with aberrant activation of NF-κβ, JNK, and Wnt/β-catenin signaling pathways. Although microglial involvement in SCA1 remains less well understood, microglial activation appears to be regionally re-stricted to the cerebellum and inferior olive. Studies of microglial depletion have yielded partial and, in some cases, conflicting functional outcomes. Notably, dysregulated Wnt/β-catenin signaling across all three glial subtypes may represent a unifying mechanism. Together, these findings identify glia as active, region-specific contributors to SCA1 pathogenesis and highlight underexplored opportunities for mechanistic and therapeutic investigation in polyglutamine diseases.