Amyloid propagation in a sporadic model of Alzheimer's disease: Development of new models and analysis methods/seeding and spreading of proteinopathies. (7th December 2020)

• Record Type: Journal Article
• Authors: Huynh, Kelly Do; Nguyen, Marie Minh Thu; Cheung, Alwin; Tran, Janine Pham; Nuñez‐Diaz, Cristina; Forner, Stefania; Martini, Alessandra Cadete; Trujillo‐Estrada, Laura; Da Cunha, Celia; Shahnawaz, Mohammad; Soto, Claudio; Moreno‐Gonzalez, Ines; Gutierrez, Antonia; LaFerla, Frank; Baglietto‐Vargas, David
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.045657
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Most age‐associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer's disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion‐like process of template protein corruption or seeding. In fact, studies in FAD‐based animal models show that Aβ deposition and cerebral amyloid angiopathy may be induced by intracerebral infusion of brain extracts from AD patients or from aged APP‐transgenic mice. These studies have shown that the characteristic of both the seeding agent and the host influence the pathologic signature of the Aβ seeds. In this regard, the majority of the Aβ‐seeding studies have been done in APP‐transgenic animal models that overproduce APP and/or Aβ. However, it remains to be elucidated whether Aβ deposition can be induced by Aβ seeds in an animal model that does not overexpress APP and produces wild type human Aβ and if these aggregates are similar to the human condition. Method: Here, we used an innovative animal model to better understand the amyloidogenic events that occur in the sporadic form of the disease. Our model, termed hAβ‐KI, expresses wild‐type human Aβ under the control of the endogenous mouse APP gene. Thus, amyloid seeds from AD patients (stage C for amyloid) from the Alzheimer's Disease Research Center (ADRC) at UCI were administered into 7‐8‐month‐old hAβ‐KI and as positive controls 3xTg‐AD mice were employed. Result: Our findings demonstrated that amyloid seeds can stimulate Aβ aggregations in both models (the 3xTg‐AD and the hAb‐KI). Moreover, we found that Aβ aggregates occur earlier in the 3xTg‐AD vs hAb‐KI and that a longer term of treatment is necessary to accelerate diffusible Aβ pathology in the hAb‐KI mice. Conclusion: This knockin model represents an important first step towards the development of next‐generation animal models that hopefully will provide better predictive outcomes for human patients, which can turn into safe and effective clinical applications.