Astrocytic ablation of truncated TrkB receptors reduces amyloid plaques and prevents synaptic loss in 5xFAD mice
- 1The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida
Abstract
Brain-derived neurotrophic factor (BDNF) is essential for nervous system development and function and exerts its effects primarily through the tropomyosin receptor kinase B (TrkB). The Ntrk2 gene encodes a full-length receptor (TrkB.FL) and two truncated isoforms (TrkB.T1 and TrkB.T2, collectively TrkB.T) that lack the intracellular tyrosine kinase domain. TrkB.T is expressed predominantly in astrocytes and is thought to inhibit BDNF-TrkB.FL signaling by sequestering BDNF and forming signaling-deficient heterodimers with TrkB.FL. Here, we investigated whether selective ablation of astrocytic TrkB.T could ameliorate Alzheimer's disease (AD) pathology by enhancing endogenous BDNF-TrkB.FL signaling. Astrocyte-specific deletion of the Ntrk2 gene at 5 weeks of age reduced cortical TrkB.T expression by more than 80% without affecting TrkB.FL levels. TrkB.T ablation increased the size of Bassoon-positive presynaptic active zones, consistent with enhanced BDNF-TrkB.FL signaling. Remarkably, astrocytic TrkB.T ablation reduced {beta}-amyloid plaque burden by more than 60% in the cortex, hippocampus, and subiculum of 6-month-old 5xFAD mice, despite having no detectable effect on microgliosis or astrogliosis. Furthermore, TrkB.T ablation prevented reductions in the density and size of PSD-95-positive postsynaptic sites in the cortex and hippocampus of 5xFAD mice at 1 year old. Together, these findings identify astrocytic TrkB.T as an important regulator of amyloid pathology and synaptic integrity in an AD mouse model. Our results suggest that selectively reducing TrkB.T expression represents a promising therapeutic strategy to enhance endogenous neuroprotective BDNF-TrkB.FL signaling, reduce amyloid pathology, and preserve synaptic integrity in AD.
Related
- Impaired astrocytic Cx43 syncytial network in lateral habenula affects synaptic connectivity and drives adolescent stress-induced depression
- An astrocytic AMPAR-dependent parity signal preserves synaptic strength
- Spatiotemporal co-regulation of IL2 and TCR receptors reveals early antigen-driven synaptic synergy in human CD8+ T cells
- GABAB Receptors Gate Sex-Specific Synaptic Plasticity in the Nucleus Accumbens
- Selective excitatory effects of γ‐glutamyl‐glycine, a glutathione metabolite, on GluN1 NMDA and mGlu5 receptors impacting synaptic plasticity
BibTeX
@misc{bass2026astrocytic,
title = {{Astrocytic ablation of truncated TrkB receptors reduces amyloid plaques and prevents synaptic loss in 5xFAD mice}},
author = {R. Bass and H. Masterson and Y. Chen and B. Xu},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.20.760443},
url = {https://www.biorxiv.org/content/10.64898/2026.10.20.760443v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Astrocytic ablation of truncated TrkB receptors reduces amyloid plaques and prevents synaptic loss in 5xFAD mice
AU - R. Bass
AU - H. Masterson
AU - Y. Chen
AU - B. Xu
PY - 2026
DA - 2026/10/20
PB - bioRxiv
DO - 10.64898/2026.10.20.760443
UR - https://www.biorxiv.org/content/10.64898/2026.10.20.760443v1
AB - Brain-derived neurotrophic factor (BDNF) is essential for nervous system development and function and exerts its effects primarily through the tropomyosin receptor kinase B (TrkB). The Ntrk2 gene encodes a full-length receptor (TrkB.FL) and two truncated isoforms (TrkB.T1 and TrkB.T2, collectively TrkB.T) that lack the intracellular tyrosine kinase domain. TrkB.T is expressed predominantly in astrocytes and is thought to inhibit BDNF-TrkB.FL signaling by sequestering BDNF and forming signaling-deficient heterodimers with TrkB.FL. Here, we investigated whether selective ablation of astrocytic TrkB.T could ameliorate Alzheimer's disease (AD) pathology by enhancing endogenous BDNF-TrkB.FL signaling. Astrocyte-specific deletion of the Ntrk2 gene at 5 weeks of age reduced cortical TrkB.T expression by more than 80% without affecting TrkB.FL levels. TrkB.T ablation increased the size of Bassoon-positive presynaptic active zones, consistent with enhanced BDNF-TrkB.FL signaling. Remarkably, astrocytic TrkB.T ablation reduced {beta}-amyloid plaque burden by more than 60% in the cortex, hippocampus, and subiculum of 6-month-old 5xFAD mice, despite having no detectable effect on microgliosis or astrogliosis. Furthermore, TrkB.T ablation prevented reductions in the density and size of PSD-95-positive postsynaptic sites in the cortex and hippocampus of 5xFAD mice at 1 year old. Together, these findings identify astrocytic TrkB.T as an important regulator of amyloid pathology and synaptic integrity in an AD mouse model. Our results suggest that selectively reducing TrkB.T expression represents a promising therapeutic strategy to enhance endogenous neuroprotective BDNF-TrkB.FL signaling, reduce amyloid pathology, and preserve synaptic integrity in AD.
ER -