Modest reduction in beta-amyloidogenic processing of APP may be a viable strategy to prevent Alzheimer’s disease
Modest reduction in beta-amyloidogenic A new study by researchers at the University of Eastern Finland has shown that the APP A673T genetic variant, which protects against Alzheimer’s disease, alters the levels of several proteins and is associated with amyloid-beta metabolism in human biofluids and cell culture models. has occurred, including amyloid beta. on one’s own.
These new data support the idea that even a modest reduction in beta-amyloidogenic processing of APP may be a viable strategy for the prevention of Alzheimer’s disease.
Alzheimer’s disease (AD) is the most common form of dementia with more than 40 million people affected worldwide. The two major pathological features of AD are amyloid plaques, which are composed of toxic amyloid-beta (Aβ) peptides, and neurofibrillary tangles,
which contain hyperphosphorylated tau protein. Even though these molecular features have been known for decades,
There have been several setbacks in the development of therapies for the effective prevention or treatment of AD. However, recent clinical trials targeting different stages of Aβ aggregation have shown promise in slowing disease progression. Aβ is part of the amyloid precursor protein (APP) and is produced upon sequential proteolytic cleavage of APP.
In 2012, researchers in Iceland discovered a genetic variant within 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 show lower levels of Aβ in plasma compared with control individuals.
As the discovered APP A673T variant is very rare and almost exclusively found in Nordic populations, there are only a few studies on its effects and mechanisms.
In the current study, the researchers analyzed the cerebrospinal fluid (CSF) and plasma of APP A673T carriers and control individuals using mass spectrometry-based proteomics, which identified changes in protein levels between study groups in an unbiased manner. allows. In addition, the APP A673T variant was introduced into 2D and 3D neuronal cell culture models with pathogenic APP mutations.
The study reports for the first time the protective effects of the APP A673T variant against AD-associated changes in CSF, plasma, and brain biopsy samples from carriers of the genetic variant. CSF levels of Aβ42 and soluble APP-beta (sAPPβ),
which is another metabolite of beta-amyloidogenic processing of APP, was significantly reduced in APP A673T carriers as compared to well-matched controls not carrying the protective variant.
Unbiased proteomics approaches from CSF and plasma samples of APP A673T carriers identified differences in the levels of several proteins and peptides that are involved in protein phosphorylation, inflammation and mitochondrial function. Importantly, some of the identified key targets showed an inverse correlation in postmortem brain tissues of 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 A673T variant resulted in strong changes in APP processing products. In accordance with the CSF results, SAPPβ levels in particular were lower in all models expressing APP A673T, often accompanied by decreased levels of Aβ42.
These results demonstrate the effectiveness of the protective APP A673T variant to shift APP processing from beta-amyloidogenic toward the non-amyloidogenic pathway even in the presence of two pathogenic APP mutations.
Journal reference:
Vitraham, R., et al. (2023) The protective Alzheimer’s disease-associated APP A673T variant significantly reduces SAPPβ levels in cerebrospinal fluid and 2D/3D cell culture models. Neurobiology of disease. doi.org/10.1016/j.nbd.2023.106140.