A study published in the journal Nature Aging on February 20, “Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits,” characterizes the effects of neuronal ApoE4 on Alzheimer disease (AD)-related pathologies in an ApoE4-expressing neurodegenerative mouse model of tauopathy. The study was led by Yadong Huang, MD, PhD, associate professor of pathology and neurology at the University of California, San Francisco (UCSF) and forms the doctoral dissertation of Nicole Koutsodendris, PhD, currently a scientist at Genetech.

Yadong Huang, MD, PhD, associate professor of pathology and neurology at the University of California, San Francisco, is the senior author of the study.

“Establishing a key role of neuronal ApoE4 in the pathogenesis of Alzheimer’s disease opens up new possibilities for developing better drugs or strategies to treat Alzheimer’s disease,” said Huang. “For instance, drugs or gene-editing strategies could be developed to block mechanisms responsible for the production of ApoE4 within neurons, therefore eliminating or lowering neuronal ApoE4 and consequently slowing down the disease.”

Late onset Alzheimer disease (AD) is associated with deposition of tau tangles, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Earlier studies have shown the ApoE4 allele confers increased risk for the disease through its diminished efficacy in removing plaques, while the ApoE2 allele decreases AD risk in comparison to the common ApoE3 allele.

Stress is known to increase neuronal APOE expression. Despite the prominent risk for late-onset AD linked to variations in APOE, the neuronal function of its disease-linked allele, APOE4, and its role in AD pathology was unclear until now.

Huang’s team has shown that the selective removal of APOE4 from neurons markedly reduces tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. The researchers also conducted single-nucleus RNA sequencing to show that the removal of neuronal ApoE4 considerably decreased subsets of neurons linked to neurodegeneration, oligodendrocytes, astrocytes and microglia.

Earlier studies on human brains have shown that ApoE4 hastens the loss of hippocampal volume, increases the burden of tau tangles, neuronal phosphorylated tau, neuroinflammation, and gliosis and decreases myelination and the integrity of white matter. Mouse model studies have parallelly shown increases in neurodegeneration, and tauopathy.

The current study comprehensively compares ApoE4- and ApoE3-expressing tauopathy mouse models to demonstrate that removing neuronal ApoE4 has wide ranging benefits, including radical reductions in the accumulation and spread of hippocampal tau, neurodegeneration and hippocampal neuron loss, myelin and oligodendrocyte deficits, neuronal hyperexcitability, microgliosis, and astrogliosis.

This study on a mouse model of tauopathy provides convincing evidence to support the role of neuronal ApoE4 in inducing the hallmark pathologies associated with AD and suggests that the therapeutic suppression of ApoE4 expression could potentially mitigate progressive neurodegeneration and other deficits associated with late onset Alzheimer’s disease.

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