New preclinical work links ectopic ERBB4 expression in excitatory neurons to early neuronal changes, synapse loss, reactive gliosis, amyloid deposition and cognitive deficits, with mTOR signalling mediating downstream effects; human transcriptomic data give conditional support while important caveats remain about mouse models.
Early-responsive excitatory neurons (EREN) expressing aberrant Erbb4 appear in Alzheimer’s mouse models and may precede major pathology.
Deleting Erbb4 in excitatory neurons prevented synapse loss, abnormal network activity, reactive gliosis, amyloid plaque buildup and cognitive deficits in those models.
Overexpressing Erbb4 in normal excitatory neurons produced core Alzheimer’s-like features without amyloid plaques, and the effects required mTOR pathway activity.
Researchers examined the role of ERBB4, a receptor tyrosine kinase (encoded by Erbb4), in Alzheimer's disease (AD) models. Using single-nucleus RNA sequencing they identified a population they call early-responsive excitatory neurons (EREN) that express ectopic Erbb4 as an early alteration in mouse models of AD.
The chain of observations supports a mechanistic sequence in the animal models: ectopic Erbb4 expression in excitatory neurons → emergence of an EREN transcriptional state → activation of mTOR-dependent signalling → synaptic dysfunction, gliosis and network abnormalities → promotion of amyloid and tau-related downstream pathology and cognitive impairment. The requirement for mTOR points to a defined intracellular pathway mediating these effects.
Human data in this study are supportive but not conclusive. Directed mediation analysis of human transcriptomes is consistent with the proposed cascade, which strengthens relevance, but it does not prove causality in humans.
If excitatory neuronal ERBB4 is an early pathogenic driver in humans, it could be a therapeutic target across neurodegenerative diseases that involve similar cascades. The mTOR dependence suggests possible intervention points downstream of ERBB4. Critical next steps are replication across additional models, mechanistic dissection in human cells or tissues, and careful evaluation of how well the mouse-model cascade maps to human disease progression.
This study puts ERBB4 overexpression in excitatory neurons forward as a potential early mechanism connecting neuronal state changes to hallmark Alzheimer's pathologies in preclinical models, and provides transcriptomic evidence in human datasets that is compatible with the model. The findings offer a focused mechanistic hypothesis and intervention points but require cautious interpretation because of limitations of current mouse models and the difference between compatibility and proof in human disease.
A study suggests that increasing SORLA protein levels could help treat Alzheimer’s disease and other disorders involving tau protein. Increasing SORLA, a protein with a protective role in the brain, helped mice withstand damage from tau tangles, the toxic protein clumps associated with Alzheimer’s disease. The findings
Two studies reveal how APOE4, a major genetic risk factor for Alzheimer’s, disrupts brain blood vessels and promotes abnormal protein accumulation, pointing to potentially reversible disease mechanisms. The post APOE4 Linked to Potentially Reversible Mechanisms of Brain Blood Vessel Damage in Alzheimer’s appeared first
The Alzheimer’s risk gene APOE4 may actively damage brain blood vessels and sabotage the cellular systems that remove harmful proteins. Researchers were able to reverse some of these effects in experiments, revealing promising new targets for Alzheimer’s, Parkinson’s, and other neurodegenerative diseases.
Why is the APOEОµ2 variant of the APOE gene associated with a lower risk of Alzheimer's disease and slightly longer life expectancy? Past research has investigated the role of APOE in cholesterol metabolism and inflammation in microglia, the innate immune cells of the brain implicated in neurodegenerative conditions. H
Many of the more sophisticated forms of medicine, including gene therapies and immunotherapies, are challenging to deliver to the brain. At the very least there are far fewer practical options for delivery, and it is possible that none of that that exist fit a given desired use case. The blood-brain barrier stands in t
Exosomes are one category of extracellular vesicle secreted by cells, a membrane-wrapped package of molecules, one complex component of the extensive, incompletely mapped communication that takes place constantly between cells. Exosome therapies are conceptually similar to stem cell therapies, an attempt to favorably a
Loading more related stories...
Open the app view to save this story, compare related coverage, and continue from the same source.