Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer’s disease

The article in 3 sentences.

5xFAD mouse model of Alzheimer’s disease has been widely used in AD research due to its close simulation of amyloidogenesis in an age-dependent manner.
The 5xFAD mouse model also mirrors AD in terms of Abeta associated behavioral level (impaired hippocampus-dependent tasks) cell level (microgliosis, astrocytosis), gene level (upregulation of inflammation-related genes, downregulation of synaptic- and neuronal function-related genes) alteration.
The 5xFAD mouse model serves as a benchmark for future AD mouse models given its detailed demonstration of AD pathology at various time points.

I had known that drug discovery for AD has been hindered by our lack of understanding of the disease’s pathogenesis. What I did not know is how such ignorance has fundamentally flawed the experiments that investigated agents were evaluated with. Without the appropriate tools, how are we supposed to expect the logical translation of animal model-based results into human applicability?
The 5xFAD mouse model is able to model the Abeta pathology of AD sufficiently. It is based on overexpression and the inclusion of autosomal dominant mutation, despite the fact that overexpression and genetic mutations do not occur in the overwhelming majority of human AD cases. This implies that we do not have the proper animal models to simulate the majority of human AD pathologies.
All that being said, generating the “correct” AD mouse model does not have to be a zero-sum game. The limited applicability of the 5xFAD mouse model does not make it wrong. It just means that we should focus on testing Abeta related pathology and Abeta-targeted treatment efficacy of this particular model. Here is the point where we should widen our perspective—a juncture to realize that there can be multiple tools in AD animal model research to explore the various facets of this multi-faceted disease, to say the least. There could be a model for mitochondrial dysfunction, a model for neurotransmitter dysfunction, and a model for neuroinflammatory dysfunction model.

The systemic phenotyping performed in this article is a splendid exploration of what we know we know. It is from this starting point that we are empowered to push the boundaries into what we know we don’t know. An interesting related article expanded our understanding of the distribution of Abeta in the various brain regions, as opposed to the commonly focused hippocampus and cerebral cortex. This is essential as the hippocampus does not operate in a standalone fashion, but rather has extensive interactions with the prefrontal cortex and the amygdala in memory formation.