Network Tau spreading is vulnerable to the expression gradients of APOE and glutamatergic-related genes

Abstract

A key hallmark of Alzheimer’s disease (AD) pathology is the intracellular accumulation of tau protein in the form of neurofibrillary tangles across large-scale networks of the human brain cortex. Currently, it is still unclear how tau accumulates within specific cortical systems and whether in situ genetic traits play a role in this circuit-based propagation progression. In this study, using two independent cohorts of cognitively normal older participants, we reveal the brain network foundation of tau spreading and its association with using high-resolution transcriptomic genetic data. We observed that specific connectomic and genetic gradients exist along the tau spreading network. In particular, we identified 577 genes whose expression is associated with the spatial spreading of tau. Within this set of genes, APOE and glutamatergic synaptic genes, such as SLC1A2 , play a central role. Thus, our study characterizes neurogenetic topological vulnerabilities in distinctive brain circuits of tau spreading and suggests that drug development strategies targeting the gradient expression of this set of genes should be explored to help reduce or prevent pathological tau accumulation.

Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

“…Of note are genes involved in the astrocytic component of tripartite synapses that are dysregulated in parallel to the stereotypical march of pTau pathology across cortical association areas. Furthermore, the negative correlation between the SLC1A2- containing synapse-enriched spatial gene set and pTau levels is consistent with the reported association between a PET-based tau-spreading network and a gradient of expression of glutamatergic synaptic genes, singularly SLC1A2 22 . Thus, these results could be indicating that astrocytes, as part of the tripartite excitatory synapses, play a key role in synaptic dysfunction and the trans-synaptic pTau propagation between excitatory neurons along vulnerable AD neural networks.…”

ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels

“…Aβ thresholds marking tau spreading may vary individually . Carriage of the apolipoprotein E ε4 (ApoE4) allele, the strongest known risk factor for sporadic AD, has been linked to abnormal Aβ-independent tau biomarker levels and cortical tau spreading patterns that closely align with cerebral APOE messenger RNA expression . Yet, ApoE4 carriage is neither linked to higher risk of developing primary tauopathies nor to spreading of age-related medial temporal lobe tau to the cortex in the absence of Aβ; therefore, tau spreading in ApoE4 carriers is seemingly associated with Aβ.…”

Chemotherapy promotes astrocytic response to Aβ deposition, but not Aβ levels, in a mouse model of amyloid and APOE

“…We did not look at mice absent of AD pathology nor mice susceptible to other major neuropathological hallmarks of AD, such as neurofibrillary tangles. APOE expression predisposed to tau spreading in human brains as correlated in tau PET analysis and transcriptome measures ( Montal et al, 2022 ). There are appropriate mouse models to test whether chemotherapy increases tau accumulation with overexpression of mutant tau in the presence of APOE3 or APOE4.…”