Thy1-ApoE4/C/EBPβ double transgenic mice act as a sporadic model with Alzheimer’s disease


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The majority of Alzheimer’s disease (AD) mouse models are developed based on genetic mutations including APP and PS1/2, for instance, the commonly used models like APP/PS1 and 3xTg AD mice. Though AD patients carry no any Tau mutation, in order to recapitulate Tau pathologies, Tau P301S mutant is included in 3xTg AD mice. Nevertheless, genetic mutations account for less than 1% of AD cases, with the majority being sporadic. Therefore, developing a mouse model that mimics sporadic AD cases is of great importance and essential for in-depth understanding of AD pathologies.

 Over the years, our group has established that the C/EBPβ/AEP pathway is a core regulatory mechanism triggering the occurrence and development of AD. On one hand, C/EBPβ, a crucial transcription factor for AEP, regulates the expression of genes essential for AD pathologies, including APP, microtubule-associated protein Tau (MAPT) and BACE1 (β-site amyloid precursor protein cleaving enzyme) (1, 2). On the other hand, it also plays an essential role in mediating transcription of AEP, which acts as a novel δ-secretase that cleaves upregulated substrates such as APP, Tau, and BACE1, generating fragments like APP N585, APP C586, BACE1 N294 and Tau N368, further accelerating the pathological formation of Aβ and Tau (3, 4). Additionally, we have found that C/EBPβ selectively promotes ApoE4 expression in neurons in AD patients, leading to Aβ clearance impairment and increased aggregation (5). ApoE4 is well known as a primary genetic risk factor for sporadic AD. Though ApoE4 is physiologically expressed in astrocytes and secreted, mounting evidence shows that ApoE4 is also expressed in neurons under stresses or pathologically (6, 7). Interestingly, ApoE4 can also synergistically activate the CEBPβ/AEP pathway through feedback with 27-hydroxycholesterol, exacerbating AD pathologies (8). Based on these findings, we hypothesize that ApoE4 elevation in neurons may drive the pathogenesis of AD by activating the CEBPβ/AEP pathway.


To validate this hypothesis, we developed a double-transgenic mouse model expressing human ApoE4 and C/EBPβ specifically in neurons under the Thy1 promoter (i.e., Thy1-ApoE4/C/EBPβ), and compared the mice with 3xTg AD mouse model side by side. We performed the study by using the “four golden standards” of clinical AD diagnosis, namely, behavioral test, MRI, PET imaging, and CSF analysis. Our results reveal that Thy1-ApoE4/C/EBPβ mice show gradual decline in cognitive and learning memory functions in an age-dependent manner, similar to 3xTg mice. Further, MRI analysis illustrates a progressive decrease in the brain volume, accompanied by augmented Aβ and Tau pathology as validated by PET imaging. In addition, a decrease in the Aβ42/Aβ40 ratio was observed in CSF. Furthermore, this study extensively compared the pathways of Ab and Tau pathology propagation in 3xTg mice and Thy1-ApoE4-C/EBPβ mice, and conducted functional studies both in vitro and in vivo by extracting aggregates of Ab and Tau from these two mouse models. We found that the endogenous mouse Ab and Tau pathology propagation pathways and functions in Thy1-ApoE4-C/EBPβ mice are similar to those human counterparts in 3xTg AD mice. 

Overall, this study demonstrated that Thy1-ApoE4/C/EBPβ mice, carrying no any genetic mutations, gradually develop the pathological features of AD tempo-spatially, establishing an ideal sporadic AD mouse model that mimics human AD patient pathologies. Conceivably, it provides a powerful tool for analyzing AD pathogenesis and drug development for interfering with AD. 


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