Discovery of Shanghai APP Mutation Offers New Avenues for Treatment of Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting tens of millions of people worldwide, and it is the most common cause of dementia. Early-onset AD is typically associated with mutations in the genes APP, PSEN1, and PSEN2, leading to a more aggressive form of the disease with atypical symptoms. In contrast, the newly discovered "Shanghai APP" mutation has been linked to LOAD, which affects a larger population of AD patients.

In a study published in Genes & Diseases on 10 April 2023, researchers from Ruijin Hospital, affiliated to Shanghai Jiao Tong University School of Medicine and other three teams detected the Shanghai APP mutation in a Chinese patient who developed memory decline in his mid-70s. Neuroimaging techniques confirmed the presence of widespread amyloid β deposition, a key hallmark of AD. Using molecular dynamics simulation and in vitro experiments, the team found that the E674Q mutation led to increased processing of APP and production of amyloid β, a toxic protein linked to AD. Additionally, the biochemical aggregation experiments suggested that the E674Q peptide exhibited higher aggregation than the wild-type peptide, especially the formation of filaments that hinged several fibrils.

To further investigate the mutation's effects in vivo, the researchers introduced the E674Q mutant APP gene into the hippocampi of two-month-old mice using adeno-associated virus (AAV) gene transfer. The study revealed that the E674Q mutation resulted in impaired learning behavior and increased pathological burden in the mouse model, demonstrating its pathogenic role in AD. The E674Q substitution exhibited a strong amyloidogenic effect, and, to the researchers' knowledge, it is the only known pathogenic mutation within the amyloid processing sequence causing LOAD. This finding is significant, as it may open up new avenues for understanding the development of LOAD and lead to more effective treatments for patients suffering from this form of Alzheimer's disease.

The discovery of the novel Shanghai APP mutation provides a unique opportunity to delve deeper into the molecular mechanisms underlying LOAD. Further research into the effects of the E674Q mutation is essential to explore the potential development of targeted therapies or interventions that may slow or halt the progression of AD. By understanding how this specific mutation contributes to the onset and progression of LOAD, scientists may be able to devise new strategies for preventing or treating this devastating disease, ultimately improving the quality of life for tens of millions of patients and their families.

Source:
Journal reference:

Zhang, Y., et al. (2023). E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer’s disease. Genes & Diseases. doi.org/10.1016/j.gendis.2023.02.051.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of AZoLifeSciences.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Novel Approach to Combat Protein-Related Diseases