BARCELONA, Spain — The majority of research dedicated to understanding and treating Alzheimer’s disease has been, understandably, focused on the brain. Now, however, new research out of Spain conducted at the Autonomous University of Barcelona is lending further credence to the hypothesis that oxidative stress and inflammation, in combination with the natural aging process, may play an important role in the development of dementia. According to the theory, the liver could be a key, yet overlooked, organ in the development and prognosis of Alzheimer’s disease, the most common form of dementia.
The liver is an integral bodily organ, responsible for regulating metabolism and supporting the immune system.
A research team from the UAB Institut de Neurociències led by Professor Lydia Giménez-Llort from the UAB Department of Psychiatry and Legal Medicine, in collaboration with Professor Josep Reig-Vilallonga from the UAB Department of Morphological Sciences, investigated this hypothesis by comparing Alzheimer’s disease mice models with a group of control rodents of the same advanced age and sex.
Subsequent findings uncovered several features of liver dysfunction among diseased mice; hepatomegaly (enlarged liver), histopathological amyloidosis (abnormal protein deposits in tissues), oxidative stress, and cellular inflammation.
Recently, in another study authored by the same research group, scientists highlighted the involvement of the peripheral organs in Alzheimer’s, and their importance in the psychological aspects of its pathology. This latest work showcases that there are alterations in the liver-brain axis, related to behavioral changes like increased neophobia (fear of novelty), as well as dysfunctions in the hypothalamic-pituitary-adrenal axis (HPA), known to regulate stress responses.
”We saw that diseased mice presented larger livers, and when we examined them under the microscope, we realized they had liver pathology in the form of amyloidosis. That is why we decided to deepen the study of the alterations that could be occurring in the liver and in the liver-brain relationship, which has been rarely studied until now,” explains Juan Fraile, a researcher at the Institut de Neurociències and first author of the article, in a media release.
“The histopathological evaluation of the control mice samples also provided new data regarding the aging process. Hepatic steatosis was the distinguishing feature in the livers of these animals, and in the male sex it was associated with obesity,” adds Prof. Josep Reig-Vilallonga.
The liver’s involvement when it comes to the cleaning of the b-amyloid protein, which accumulates in the brain of Alzheimer’s patients, is well established. Moreover, possible inflammatory communications through pro-inflammatory factors between these two organs have also been noted. This is particularly important for older ages, as that’s when the blood-brain barrier becomes more permeable, allowing the periphery and the brain to be in closer contact. At that point, via its detoxification function, the liver becomes saturated and increases its inflammation and oxidative stress, worsening neuro-inflammation and oxidative stress in the nervous system.
Additionally, besides age, researchers demonstrated that gender (male) and isolation (especially when it is unwanted) can influence the progression of hepatomegaly, oxidative stress, and inflammation, consequently leading to the worsening of the prognosis of the disease.
“The liver-brain axis alterations and liver dysfunction observed in the diseased animals in our study open new paths to understanding the systemic aspects of this complex disease, and facilitate the identification of potential targets for further research, including the perspective of sex/gender and the impact of loneliness,” Dr. Giménez-Llort concludes.
Study authors believe hepatic oxy-inflammation and neophobia represent potential targets of systems integration in Alzheimer’s disease research, with focus points including intrinsic factors like genotype and gender, as well as extrinsic factors, such as social conditions. This project marks a major breakthrough in modern science’s understanding of Alzheimer’s disease, highlighting the urgent need to expand research efforts beyond just the brain and incorporate peripheral organs and systemic factors.
The study is published in the journal Cells.
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