Deconstructing Alzheimer’s Disease: How to Bridge the Gap between Experimental Models and the Human Pathology?

Abstract

Discovered more than a century ago, Alzheimer’s disease (AD) is not only still present in our societies but has also become the most common dementia, with 50 million people worldwide affected by the disease. This number is expected to double in the next generation, and no cure is currently available to slow down or stop the disease progression. Recently, some advances were made due to the approval of the aducanumab treatment by the American Food and Drug Administration. The etiology of this human-specific disease remains poorly understood, and the mechanisms of its development have not been completely clarified. Several hypotheses concerning the molecular mechanisms of AD have been proposed, but the existing studies focus primarily on the two main markers of the disease: the amyloid β peptides, whose aggregation in the brain generates amyloid plaques, and the abnormally phosphorylated tau proteins, which are responsible for neurofibrillary tangles. These protein aggregates induce neuroinflammation and neurodegeneration, which, in turn, lead to cognitive and behavioral deficits. The challenge is, therefore, to create models that best reproduce this pathology. This review aims at gathering the different existing AD models developed in vitro, in cellulo, and in vivo. Many models have already been set up, but it is necessary to identify the most relevant ones for our investigations. The purpose of the review is to help researchers to identify the most pertinent disease models, from the most often used to the most recently generated and from simple to complex, explaining their specificities and giving concrete examples.

Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease

“…Sections were washed twice in an ice-cold HEPES buffer 50 mM (pH 7.4), dipped in distilled water, and air-dried. Sections were exposed to Kodak Biomax MR films (Sigma, St. Louis, MO, USA) together with 14 C standards for 48 h at 4 • C.…”

“…However, some animal models have been developed and must be compared to AD patients for their validation. In addition, the translational research based on "omics" technologies (including lipidomics) are increasing our knowledge of AD for the identification of early AD biomarkers [14].…”

The role of massive demographic databases in intractable illnesses: Denomics for dementia

“…In order to move from the conceptual to the pragmatic, the aggregate findings of the exposome, denome and genome must be tested in appropriate living models which may include animal and cell culture systems [39] , [40] . These systems can be used to develop and test treatments or prophylaxis for AD.…”

Nutritional assessment models for Alzheimer's disease: Advances and perspectives

“…Furthermore, the cell model is considered to be one of the effective means to study AD. AD‐related nerve cells were isolated from human or mouse sources and cultured in 2D and 3D systems to induce overexpression of the APP gene or hyperphosphorylation of tau in different ways, resulting in the pathological characteristics of AD in these cell models (Vignon et al., 2021). Additionally, cell models are widely used due to their abundant sources, few interference factors, and ease of control.…”