Mouse models expressing human genes implicated in Alzheimer’s disease provided valuable insights into disease progression^[1]. In a recent article, researchers used these models to study the accumulation of amyloid-beta plaques and tau protein tangles—hallmarks of Alzheimer’s disease.

The P301S Tau Model: Linking Gut Microbiota and Neurodegeneration

One prominent model is the P301S tau transgenic mice, which express the human tau mutations associated with frontotemporal dementia and Alzheimer's. Researchers using this model have found that gut microbiota is critical in tau-mediated neurodegeneration, with the ApoE4 isoform exacerbating the effects, critically, manipulating the gut microbiota through germ-free conditions or antibiotic treatment reduced neurodegeneration in an ApoE-dependent manner. This study underscores the growing importance of the gut-brain axis in Alzheimer’s disease, where dysbiosis can accelerate neurodegeneration, potentially opening new therapeutic avenues targeting microbiota to modulate progression^[2].

Myelin Dysfunction: A Key Driver of Amyloid-Beta Accumulation

Another notable development involved the discovery of the role of myelin dysfunction in driving amyloid-β (Aβ) deposition, a hallmark of Alzheimer’s disease. Researchers used two main mouse models of AD, 5×FAD a well-established model of Alzheimer’s disease that mimics amyloid plaque formation and neurodegeneration, and APPNLGF, which carries mutations in the human amyloid precursor protein (APP gene), to explore how genetic mutations leading to myelin disintegration (in Cnp−/− and Plp−/y mice) exacerbate Aβ plaque formation. These models demonstrated that myelin defects not only increased amyloid plaque load, especially in the hippocampal white matter and cortex, but also altered microglial responses, which are typically involved in clearing plaques. The study suggested that improving myelin integrity could help delay disease progression^[3].

APP/PS1 Model: Immune Dysregulation and Neuronal Damage

The APP/PS1 model has also provided valuable insights, particularly in identifying the critical role of immune system dysregulation in neurodegeneration. Studies have shown that microglial and T-cell interactions exacerbate neuronal damage, particularly in regions rich in tau pathology, highlighting the potential for immunomodulatory treatments ^[4].

Stem Cell Therapy: TREM2-Engineered HSPCs in 5xFAD Mice

On the translational side, mice were used to test the efficacy of a promising intracerebral hematopoietic stem cell (HSPC) gene therapy in Alzheimer’s disease, using the 5xFAD mouse model. Researchers transplanted HSPCs engineered to overexpress TREM2, a receptor known for enhancing microglial response to neurodegeneration, into the brain of 5xFAD mice. The study demonstrated that these engineered HSPCs reduced amyloid-beta (Aβ) plaques, decreased neuroinflammation, and improved cognitive function in the treated mice. This proof-of-concept highlights the potential of stem cell therapy in treating severe neurodegenerative disorders^[5].

Overall, the use of these genetically engineered mouse models in recent years has provided deeper mechanistic insights into AD pathology, focusing on the interplay between genetic risk factors like ApoE4, myelin integrity, and the immune system’s role in neurodegeneration. These models continue to be indispensable in the search for effective disease-modifying therapies.

[1] Zhong MZ, Peng T, Duarte ML, Wang M, Cai D. Updates on mouse models of Alzheimer's disease. Mol Neurodegener. 2024 Mar 11;19(1):23. doi: 10.1186/s13024-024-00712-0. PMID: 38462606; PMCID: PMC10926682.

[2] Seo DO, O'Donnell D, Jain N, Ulrich JD, Herz J, Li Y, Lemieux M, Cheng J, Hu H, Serrano JR, Bao X, Franke E, Karlsson M, Meier M, Deng S, Desai C, Dodiya H, Lelwala-Guruge J, Handley SA, Kipnis J, Sisodia SS, Gordon JI, Holtzman DM. ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Science. 2023 Jan 13;379(6628):eadd1236. doi: 10.1126/science.add1236. Epub 2023 Jan 13. PMID: 36634180; PMCID: PMC9901565.

[3] Depp C, Sun T, Sasmita AO, Spieth L, Berghoff SA, Nazarenko T, Overhoff K, Steixner-Kumar AA, Subramanian S, Arinrad S, Ruhwedel T, Möbius W, Göbbels S, Saher G, Werner HB, Damkou A, Zampar S, Wirths O, Thalmann M, Simons M, Saito T, Saido T, Krueger-Burg D, Kawaguchi R, Willem M, Haass C, Geschwind D, Ehrenreich H, Stassart R, Nave KA. Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease. Nature. 2023 Jun;618(7964):349-357. doi: 10.1038/s41586-023-06120-6. Epub 2023 May 31. PMID: 37258678; PMCID: PMC10247380.

[4] Chen X, Firulyova M, Manis M, Herz J, Smirnov I, Aladyeva E, Wang C, Bao X, Finn MB, Hu H, Shchukina I, Kim MW, Yuede CM, Kipnis J, Artyomov MN, Ulrich JD, Holtzman DM. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature. 2023 Mar;615(7953):668-677. doi: 10.1038/s41586-023-05788-0. Epub 2023 Mar 8.

[5] Milazzo R, Montepeloso A, Kumar R, Ferro F, Cavalca E, Rigoni P, Cabras P, Ciervo Y, Das S, Capotondo A, Pellin D, Peviani M, Biffi A. Therapeutic efficacy of intracerebral hematopoietic stem cell gene therapy in an Alzheimer's disease mouse model. Nat Commun. 2024 Sep 13;15(1):8024. doi: 10.1038/s41467-024-52301-w. PMID: 39271711; PMCID: PMC11399302.

Insights into Neurodegenerative Diseases: Alzheimer’s Disease Progression and Treatments

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