A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology.

Excitatory neurons are preferentially impaired in early Alzheimer's disease but the pathways contributing to their relative vulnerability remain largely unknown. Here we report that pathological tau accumulation takes place predominantly in excitatory neurons compared to inhibitory neurons, not only in the entorhinal cortex, a brain region affected in early Alzheimer's disease, but also in areas affected later by the disease. By analyzing RNA transcripts from single-nucleus RNA datasets, we identified a specific tau homeostasis signature of genes differentially expressed in excitatory compared to inhibitory neurons. One of the genes, BCL2-associated athanogene 3 (BAG3), a facilitator of autophagy, was identified as a hub, or master regulator, gene. We verified that reducing BAG3 levels in primary neurons exacerbated pathological tau accumulation, whereas BAG3 overexpression attenuated it. These results define a tau homeostasis signature that underlies the cellular and regional vulnerability of excitatory neurons to tau pathology

Amyloid-β-independent regulators of tau pathology in Alzheimer disease

The global epidemic of Alzheimer disease (AD) is worsening, and no approved treatment can revert or arrest progression of this disease. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Genetic data, as well as autopsy and neuroimaging studies in patients with AD, indicate that Aβ plaque deposition precedes cortical tau pathology. Because Aβ accumulation has been considered the initial insult that drives both the accumulation of tau pathology and tau-mediated neurodegeneration in AD, the development of AD therapeutics has focused mostly on removing Aβ from the brain. However, striking preclinical evidence from AD mouse models and patient-derived human induced pluripotent stem cell models indicates that tau pathology can progress independently of Aβ accumulation and arises downstream of genetic risk factors for AD and aberrant metabolic pathways. This Review outlines novel insights from preclinical research that implicate apolipoprotein E, the endocytic system, cholesterol metabolism and microglial activation as Aβ-independent regulators of tau pathology. These factors are discussed in the context of emerging findings from clinical pathology, functional neuroimaging and other approaches in humans. Finally, we discuss the implications of these new insights for current Aβ-targeted strategies and highlight the emergence of novel therapeutic strategies that target processes upstream of both Aβ and tau