ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

By Yang Shi, Kaoru Yamada, S. A. Liddelow, Scott t. Smith, Lingzhi Zhao, Wenjie Luo, Richard M. Tsai, S. Spina, Lea Teneholz Grinberg, J. Rojas and 23 more. Nature, 2017

1,058 citations recorded by the source corpus.

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.

Subfields: Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/a499c5debc099f2821afcb95fbc1b7f7754a6b25

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In Neurology

1. J. Long
2. D. Holtzman
3. M. Hasegawa

In Physiology

1. J. Long
2. Harald Hampel
3. Dan Xiao
4. Weifeng Zhang
5. Haibin Xia
6. Q. Mao
7. D. Holtzman
8. Huaxi Xu

Citations in the corpus

• Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “APOE4 significantly aggravated tau-mediated neurodegeneration in a tauopathy mouse model and induced tau aggregates in brain, while genetic ablation of APOE attenuated tau-induced neurodegeneration [469, 470].”
• Role of neuroinflammation in neurodegeneration development (2023, background): “In addition, APOE4 was found to reduce the phagocytosis ability of glial cells, enhance microglia proinflammatory activation by Aβ plaques or tau aggregates and promote neurodegeneration in the mouse models.(176,177) Although the underlying molecular mechanism is still far from clear, some clues hav”
• Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease (2018, background): “Recently, however, P301S tau transgenic mice were generated on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, and developed significant brain atrophy primarily in the hippocampus, piriform/entorhinal cortex, and amygdala, accompanied by significant lateral ventricular enlargemen”
• The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. (2018, background): “, 1995) followed by the "4 allele of apolipoprotein E (APOE "4) (Liu et al., 2013; Shi et al., 2017), and probably also cardiovascular and”
• Hallmarks of neurodegenerative diseases. (2023, neutral): “240,241 Along the same lines, GRN expression increases microgliosis and synaptic pruning, leading to hyperexcitability.”
• Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, positive): “, 2017b) suggest that lowering ApoE levels reduces relevant pathology in both amyloidosis and tauopathy mouse models (Shi et al., 2017).”