The discovery of the genetic variation offers hope for Alzheimer’s prevention

A new study conducted by researchers at the University of Eastern Finland found that the genetic variant APP A673T, which protects against Alzheimer’s disease (AD), alters the levels of several proteins and peptides linked to amyloid-beta metabolism in human biofluid and cell culture models, including beta amyloid itself.

These new data support the notion that modest reduction in beta-amyloidogenic processing of APP may be a viable strategy for Alzheimer’s disease prevention.

Alzheimer’s disease is the most common form of dementia with more than 40 million people affected worldwide. Two of the major pathological features of AD are amyloid plaques, composed of the toxic amyloid-beta (Aβ) peptide, and neurofibrillary tangles, composed of hyperphosphorylated tau protein. Although these molecular characteristics have been known for decades, there have been many setbacks in the development of therapies for the prevention or effective treatment of Alzheimer’s disease.

However, recent clinical trials targeting various steps of Aβ aggregation have shown promise in slowing disease progression. Aβ is part of the amyloid precursor protein (APP) and is generated by sequential proteolytic cleavage of APP. In 2012, researchers from Iceland discovered a genetic variant in the APP gene that protects its carriers from AD. Consequently, a previous study conducted at the University of Eastern Finland found that carriers of the APP A673T variant exhibited lower levels of Aβ in plasma compared to control individuals. Because the discovered variant of APP A673T is extremely rare and almost exclusively found in the Nordic population, there has been little research into its effects and mechanisms.

Study details

In this study, the researchers analyzed cerebrospinal fluid (CSF) and plasma of APP A673T carriers and control individuals using mass spectrometry-based proteomics, which allowed identification of changes in protein levels between study groups in an impartial manner. The APP variant A673T was introduced to 2D and 3D neural cell culture models along with the pathogenic APP mutation. The study reports for the first time, the protective effect of variant APP A673T against AD-related changes in CSF, plasma, and brain biopsy samples from carriers of the genetic variant.

The levels of CSF Aβ42 and soluble APP-beta (sAPPβ), which are other metabolites of beta-amyloidogenic processing of APP, were significantly decreased in the APP A673T carriers compared to matched controls that did not carry the protective variant. An unbiased proteomic approach of CSF and plasma samples of APP A673T carriers identified differences in the levels of several proteins and peptides closely involved in protein phosphorylation, inflammation, and mitochondrial function. Importantly, several key targets identified showed an inverse correlation in postmortem brain tissue from AD patients with respect to disease severity.

In 2D and 3D neuronal cell culture models expressing two strong AD-causing APP mutations, the introduction of the APP variant A673T resulted in robust changes in the product of APP processing. In line with the results from the CSF, in particular the sAPPβ levels were lower in all models expressing APP A673T, often accompanied by reduced Aβ42 levels. These results demonstrate the effectiveness of the protective variant APP A673T to shift APP processing from beta-amyloidogenic to non-amyloidogenic pathways even in the presence of two pathogenic APP mutations.

Viable strategy for Alzheimer’s prevention

In summary, these findings emphasize that modest reduction in beta-amyloidogenic processing of APP may be a viable strategy for the prevention of Alzheimer’s disease. Moreover, unbiased proteomic analysis sheds light on specific targets and pathways, which may play a key role in AD development. The results are published in Neurobiology of Disease.

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