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


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.






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Publication Info

Shi, Yang, Kaoru Yamada, Shane Antony Liddelow, Scott T Smith, Lingzhi Zhao, Wenjie Luo, Richard M Tsai, Salvatore Spina, et al. (2017). ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature, 549(7673). pp. 523–527. 10.1038/nature24016 Retrieved from https://hdl.handle.net/10161/15694.

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Patrick Sullivan

Associate Professor Emeritus of Medicine

The primary focus of my lab is to investigate the relationship between APOE genotype and late onset Alzheimer’s disease (AD).  The single most common and influential gene in AD is the APOE gene.  The APOE gene is polymorphic; encoding three different alleles designated APOE2, E3 or E4.  APOE4 carriers have the highest risk for AD while APOE3 carriers have an essentially neutral risk and APOE2 carriers may be protected against AD.  The APOE4 gene is also linked to increased risk for atherosclerosis, cerebral amyloid angiopathy, peripheral neuropathy, multiple sclerosis, stroke and type II diabetes; as well as an increased susceptibility to HIV and Chlamydia infections, head injury and cognitive decline following coronary bypass surgery.  The fact that 28% of the US population are carriers of the APOE4 gene, underscores the need for a better understanding of APOE’s relationship to disease.  The major challenge facing researchers today is determining why some APOE4 carriers succumb to disease while others do not.  Genetic modifiers and environmental risk factors likely explain different individual outcomes. The primary environmental risk factors are thought to be; a Westernized diet, low physical activity, chronic stress, poor sleep habits, andro/menopause and most importantly, age.

We are currently working to test novel drug formulations that specifically target putative apoE dependent mechanisms involved in neurodegeneration.  Our initial screens involve neuronal-glial cell culture models that eventually will lead to testing in animals.  We currently use the best available animal model of apoE-linked AD, the human apoE targeted replacement (TR) or “knock in” mice.  I created three lines of human apoE TR mice, each expressing one the three human apoE isoforms and have since made multiple crosses to other AD related genes (e.g. APP, PS1 and tau).  I have given the apoE TR mice and made the crosses available to over 70 labs worldwide.

We are also working to build a better model of late onset AD by combining the apoE TR mice with non-mutated human APP and tau KI mice.  We think this is important because over 98% of all AD cases contain no mutations in the APP or tau genes.  Our hope is to better understand the true etiology and progression of late onset AD.  If successful this new model should aid in both novel target identification and new drug testing to produce therapeutics with greater efficacy in treating AD.

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