A new review was published in Current Opinion in Neurobiology, by the Neuronal Trafficking in Aging, about the role of amyloid precursor protein (APP) regulation in aging.
The two authors, Cláudia Guimas de Almeida - principal investigator of the same lab - and Tatiana Burrinha talked with us about the importance of this research.
What led you to prepare and publish this review?
Our aim was to integrate the most recent knowledge on the membrane trafficking, meaning the transport of molecules intracellularly, of the amyloid precursor protein (APP), given APP’s importance as a precursor of amyloid-beta (Aβ), an important player in Alzheimer’s disease. The review of the trafficking alterations with aging was fueled by our recent discovery that the process of aging changes APP membrane trafficking. We focused on APP trafficking in neurons, the main target of Alzheimer’s disease because it differs substantially from non-neuronal and non-polarized cells.
Why is this important?
There is a lack of effective treatment for Alzheimer’s disease, but there are anti-amyloid antibodies being evaluated for treating symptomatic patients. We believe that understanding what causes Alzheimer’s disease will provide therapeutic strategies to delay or prevent it. For the most common forms of Alzheimer’s disease or late-onset Alzheimer’s disease, the disease’s molecular and cellular mechanisms start during aging. Most of our neurons are as old as we are, but how aging impacts neurons is complex and still under investigation.
In line with this idea, our group recently found that in aged neurons, endosomal trafficking is increased, enhancing APP internalization that potentiates intraneuronal Aβ production and accumulation, ultimately leading to synaptic decline. Therefore, correcting APP trafficking specifically could be an interesting approach for Alzheimer’s disease future therapeutics.
Can you use an analogy to help us understand this field?
Many older people are usually characterized by having wrinkles, white hair, and lower energy to move and perform daily tasks. With aging, our neurons also start accumulating “wrinkles” that can be called Aβ. Older people tend to be quieter and communicate less between them due to difficulties in locomotion and memory which is kind of similar in aged neurons if we consider that the movement of proteins, such as APP, is disturbed and impacts the way neurons communicate through synapses. Therefore, modulating the movement of APP in the aged neurons might have an impact on the quality of life and mental health of the elderly.
What questions remain to be asked in this field that your group will pursue?
The biggest questions that still need to be addressed are:
- How does APP trafficking change in aged human neurons?
- What are the molecular regulators of APP trafficking in aged neurons?
- How are the membrane trafficking mechanisms used by late-onset Alzheimer’s disease genetic risk factors changed in the context of aged neurons, brains, and organisms?
- Is the trafficking of APP secretases altered with aging?
- What is the precise neuronal trafficking itinerary of APP and its processing fragments in neurons?
The review "Aging impact on amyloid precursor protein neuronal trafficking" was published and can be read in Current Opinion in Neurobiology.