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Amyloid propagation in a sporadic model of Alzheimer's disease
Author(s) -
Huynh Kelly Do,
Nguyen Marie Minh Thu,
Cheung Alwin,
Tran Janine Pham,
NuñezDiaz Cristina,
Forner Stefania,
Martini Alessandra Cadete,
TrujilloEstrada Laura,
Da Cunha Celia,
Shahnawaz Mohammad,
Soto Claudio,
MorenoGonzalez Ines,
Gutierrez Antonia,
LaFerla Frank,
BagliettoVargas David
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.045657
Subject(s) - genetically modified mouse , transgene , amyloid (mycology) , disease , amyloid precursor protein , cerebral amyloid angiopathy , alzheimer's disease , chronic wasting disease , animal model , biology , neuroscience , pathology , medicine , prion protein , gene , endocrinology , biochemistry , dementia , scrapie
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.