“Post-translational modification” (PTM) is a sweeping term in molecular biology referring to the naturally occurring chemical changes after a protein is produced. PTMs can impact everything from the structure of proteins to the way they interact within the body. In 2019, researchers discovered the process of lactylation, a PTM process that involves lactate. This process has been found to relate to crucial processes including immune regulation and tissue repair — but recent research shows that it may also be leveraged to slow the effects of Alzheimer’s disease (AD).
Scientists led by Zhifang Dong at the Children’s Hospital of Chongqing Medical University recently reported that lactate modifies specific lysines on amyloid precursor proteins, altering APP intracellular transport and limiting the production and aggregation of harmful amyloid-β in mice. Read on for more information about the research, originally published in the Journal of Clinical Investigation.
Understanding Lactylation Mechanisms
As an epigenetic regulator, lactate activates gene transcription by altering chromatin structure. Lactylation has been identified on proteins including enzymes, transcription factors, and kinases, influencing protein structure, stability, and protein-protein interactions. Numerous conditions that elevate lactate, such as inflammation, can trigger this PTM. Scientists have also identified metabolic enzymes that indirectly facilitate lactylation, as well as mechanisms that remove lactyl groups. Most recently, Dong and colleagues explored whether this PTM plays any role in AD.
Harnessing Lactyl Groups in Animal Models
First, the team used pan-lactylation antibodies, which are used to detect and study lactic acid lysine, to look for a modification of APP in patients with AD. They found much lower levels of lactylated APP in the hippocampus and frontal cortex of AD patients when compared to age-matched controls. Looking at animal models, the team found that APP lysine lactylation (APP-Kla) was notably lower in APP23/PS45 AD mice than in wild type controls. The team also found that HEK293 cells overexpressing APP with familial AD mutations showed lower APP lactylation levels. The team wrote: “Taken together, these results suggest that the expression level of APP-Kla is reduced in AD.”
Next, the researchers were tasked with mimicking this modification. To do so, they introduced an essential amino acid known as threonine to the APP, a substitution meant to mimic lactylation. The amino acid substitution prevented APP from interacting with BACE1, an enzyme involved in the production of amyloid-β. Through several more tests, the team was able to get a closer look at lactylation’s role in controlling APP transport and breakdown. Finally, researchers tested the artificial modification on animal models — specifically, 3-month-old PS45 mice. After two months, they found that mice expressing APP K612T had accumulated fewer plaques than control mice. The researchers also tested the mice using a Barnes water maze and found that they maintained spatial memory and learning at “near wild type levels.”
Armed with this knowledge, could scientists then use lactylation to slow or halt the progression of AD? It might not be that simple — but lactylation still has strong potential as a regulatory mechanism in AD progression.
To study Alzheimer’s disease, Scantox offers a variety of preclinical in vitro and in vivo models. In these models, post-translational modifications can be evaluated by several biochemical and histological approaches. Furthermore, several other typical Alzheimer’s disease-related pathologies, such as neuroinflammation, increased neurofilament light chain levels as an indicator of neurodegeneration, and vascular pathology, can be evaluated.
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