Date Published: November 28, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Ramona Belfiore, Alexis Rodin, Eric Ferreira, Ramon Velazquez, Caterina Branca, Antonella Caccamo, Salvatore Oddo.
Accumulation of amyloid‐β (Aβ) and fibrillary tangles, as well as neuroinflammation and memory loss, are hallmarks of Alzheimer’s disease (AD). After almost 15 years from their generation, 3xTg‐AD mice are still one of the most used transgenic models of AD. Converging evidence indicates that the phenotype of 3xTg‐AD mice has shifted over the years and contradicting reports about onset of pathology or cognitive deficits are apparent in the literature. Here, we assessed Aβ and tau load, neuroinflammation, and cognitive changes in 2‐, 6‐, 12‐, and 20‐month‐old female 3xTg‐AD and nontransgenic (NonTg) mice. We found that ~80% of the mice analyzed had Aβ plaques in the caudal hippocampus at 6 months of age, while 100% of them had Aβ plaques in the hippocampus at 12 months of age. Cortical Aβ plaques were first detected at 12 months of age, including in the entorhinal cortex. Phosphorylated Tau at Ser202/Thr205 and Ser422 was apparent in the hippocampus of 100% of 6‐month‐old mice, while only 50% of mice showed tau phosphorylation at Thr212/Ser214 at this age. Neuroinflammation was first evident in 6‐month‐old mice and increased as a function of age. These neuropathological changes were clearly associated with progressive cognitive decline, which was first apparent at 6 months of age and became significantly worse as the mice aged. These data indicate a consistent and predictable progression of the AD‐like pathology in female 3xTg‐AD mice, and will facilitate the design of future studies using these mice.
Alzheimer’s disease (AD) is the most common neurodegenerative disease (Alzheimer’s Association, 2016). It is characterized by the accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (LaFerla & Oddo, 2005; Querfurth & LaFerla, 2010). The former are primarily made of a small peptide called amyloid‐β (Aβ), while the latter are made of hyperphosphorylated tau (Querfurth & LaFerla, 2010). Another hallmark of AD is brain inflammation, which manifests as intense reactivity of astrocytes and microglia, and increased levels of proinflammatory cytokines such as interleukin‐1β (IL1β), interleukin‐6 (IL6), and tumor necrosis factor‐α (TNFα; Heneka et al., 2015). Clinically, AD is first associated with episodic amnesia followed by significant deficits in semantic memory and procedural memory (Mormino et al., 2009). Additional clinical manifestations such as loss of judgment, problem‐solving impairment, depression, and sleep disorders are also frequently associated with early stages of the disease (Grontvedt et al., 2018).
Animal models are invaluable tools to study mechanisms of AD pathogenesis. Most models have been generated using human mutations in the APP or PS1 genes that are associated with familial AD (LaFerla & Green, 2012). However, these mice fail to recapitulate the full spectrum of AD pathology, despite developing a high degree of Aβ plaques. In contrast, overexpression of wild‐type tau does not lead to any phenotype, while expression of a human mutant tau leads to a strong tau pathology, often associated with neurodegeneration (LaFerla & Green, 2012; Puzzo et al., 2015). In 2013, we generated the 3xTg‐AD mice, which harbor mutations in APP, PS1, and tau genes. These mice develop Aβ and tau pathology, as well as neuroinflammation and cognitive deficits (Billings, Oddo, Green, McGaugh, & LaFerla, 2005; Kitazawa, Oddo, Yamasaki, Green, & LaFerla, 2005; Oddo, Caccamo, et al., 2006; Oddo, Caccamo, Kitazawa, et al., 2003; Oddo, Caccamo, Shepherd, et al., 2003; Oddo, Vasilevko, et al., 2006). While 3xTg‐AD mice overexpress mutant tau, which is not associated with AD, they have been invaluable in understanding the interplay between Aβ and tau. Multiple reports have consistently shown that in these mice, Aβ pathology contributes to the development of tau (Oddo et al., 2007, 2008; Oddo, Billings, Kesslak, Cribbs, & LaFerla, 2004; Oddo, Caccamo, Cheng, & LaFerla, 2009; Oddo, Caccamo, et al., 2006; Oddo, Vasilevko, et al., 2006). Further, we previously showed that removing Aβ was sufficient to improve tau pathology (Oddo et al., 2004; Oddo, Caccamo, et al., 2006; Oddo, Vasilevko, et al., 2006). Similar results have been obtained from human clinical trials in which Aβ immunization led to the clearance of tau (Amin et al., 2015; Boche et al., 2010; Gilman et al., 2005). Together, these results highlight how findings in 3xTg‐AD mice in regards to Aβ and tau interaction have predicted results in humans.
The authors have no conflict of interest.
RB performed most of the experiments, analyzed the data and wrote the manuscript; AR performed the immunohistochemistry; EF performed the Morris water maze experiments; RV performed the statistical evaluation; CB contributed to the design of the experiments; AC contributed to the design of the experiments, performed the ELISA assays, and edited the manuscript; SO designed the experiments, analyzed the data and wrote the manuscript. All authors read and approved the final manuscript.