Suggesting ERBB4 Overexpression as an Important Mechanism in Alzheimer's Disease
Researchers here suggest that increased ERBB4 expression in neurons is an important driving mechanism in the onset and progression of Alzheimer's disease. One has to be cautious with such findings, even given the effort made by the researchers to show that human data is compatible with the hypothesis, because the mouse models of Alzheimer's disease in which these sorts of discovery are made are very artificial. Mice do not normal exhibit anything like Alzheimer's disease, so the models induce forms of dysfunction that result in something resembling Alzheimer's in humans. The model embodies assumptions about relevant mechanisms that may not be correct, and this is one of the reasons why progress towards therapies has been slow and painful.
Single-nucleus RNA-sequencing analysis identified the emergence of early-responsive excitatory neurons (EREN), characterized by expression of ectopic Erb-B2 receptor tyrosine kinase 4 (Erbb4), as one of the earliest major alterations in Alzheimer's disease (AD) mouse models. Selective Erbb4 deletion in AD excitatory neurons abrogated abnormal neuronal network activities and synapse loss, as well as reactive gliosis, amyloid plaque deposition and cognitive deficits. Conversely, Erbb4 overexpression in wild-type excitatory neurons recapitulated these core AD-like phenotypes without amyloid plaques.
Mechanistically, these effects required mammalian target of rapamycin (mTOR) signalling downstream of ERBB4. Subsequent transcriptomic analyses showed that excitatory neuronal Erbb4 is both necessary and sufficient to induce EREN and reactive gliosis. Directed mediation analysis of human AD transcriptomic data further support a model in which excitatory neuronal ERBB4 contributes to a pathogenic cascade that links amyloid pathology to tau propagation and cognitive decline. These findings identify aberrant Erbb4 expression in excitatory neurons as an early driver of AD pathophysiology and a potential therapeutic target across neurodegenerative diseases.