SorCS1 promotes synaptic and cognitive resilience despite amyloid pathology in Alzheimer's disease model mice
Yi, N.; Lee, A. K.; Bourojeni, F. B.; Wang, M.; Inagaki, M.; Takahashi, H.
Show abstract
Alzheimer's disease (AD) lacks effective therapies despite extensive efforts targeting amyloid {beta} (A{beta}) and its precursor processing. Synapse loss is the strongest correlate of cognitive decline, driven partly by A{beta} oligomers (A{beta}Os), which bind multiple synaptic membrane proteins including the synaptic organizer neurexin and disrupt synaptic integrity and function. The protein sorting receptor SorCS1 blocks interactions between A{beta}Os and {beta}-isoforms of neurexins ({beta}-Nrxns), but its therapeutic relevance in vivo remains unclear. Using 5xFAD mice, which overproduce A{beta}Os, combined with forebrain specific neuronal SorCS1 overexpression, we show that SorCS1 preserves working memory, synaptic integrity, and basal excitatory transmission without altering amyloid deposition, in part by restoring synaptic {beta}-Nrxn expression. SorCS1 also reduces tau hyperphosphorylation in 5xFAD synaptosomes and binds the tau kinase GSK3{beta}. These results identify SorCS1 as an AD resilience promoting factor that maintains synaptic connectivity and attenuates tau pathology, revealing a therapeutic strategy that operates independently of amyloid reduction.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Microglial and Astrocyte priming in the APP/PS1 model of Alzheimer’s Disease: increased vulnerability to acute inflammation and cognitive deficits 95%
- TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease 94%
- Neuro-Metabolic and Vascular Dysfunction as an Early Diagnostic for Alzheimer's Disease and Related Dementias. 94%
Similar papers in this journal
- Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy 97%
- TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade 96%
- Dysfunction of the episodic memory network in the Alzheimer's disease cascade 95%
Similar papers in this journal
- Small tau aggregates exhibit disease-specific molecular profiles across tauopathies 95%
- Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's Disease 95%
- Sustained TREM2 stabilization accelerates microglia heterogeneity and Abeta pathology in a mouse model of Alzheimer s disease 95%
Similar papers in this journal
- ApoE2, ApoE3 and ApoE4 Differentially Impact Multiple Signaling Pathways Regulating Synaptogenesis 97%
- Amelioration of symptomatic Alzheimer's Disease after selective impairment of p75NTR function in adult forebrainexcitatory neurons 95%
- Efficient propagation of misfolded tau between individual neurons occurs in absence of degeneration 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.