A molecule capable of reducing neurodegenerative processes in the elderly

Researchers from the Doerr Institute for Research and Education (IDOR) have just published a study
in the scientific journal Translational Psychiatry.
The paper seeks to elucidate the mechanisms associated with cognitive deficits in human aging, taking into account the role of molecules, that can combat the inflammatory processes of neurodegenerative diseases, such as Alzheimer's, and enhance the endocannabinoid system
.
The substance, known as lipoxin A4, has been studied by researchers for years, and this is the first time it has been applied to treat neurodegenerative diseases associated with aging, with potential developments
in the field of diagnostics.
The study was carried out
in collaboration with the Osvaldo Cruz Foundation (Fiocruz), the Federal University of Rio de Janeiro (UFRJ), the Federal University of Espírito Santo (UFES), the Federal University of Latin American Integration (UNILA), and the Broad Institute of MIT and Harvard University.

Inflammation is part of the body's defenses, but its uncontrolled behavior plays an important role in chronic and neurodegenerative diseases, including Alzheimer's disease
.
Among other factors, the control of the inflammatory response occurs by lipid mediators, such as lipolipids, which act on the natural resolution
of inflammation.
For example, when skin cuts "heal themselves," we witness the action of
these molecules.
This active protection also occurs in the central nervous system, but is more difficult to imagine
.
The central hypothesis of the published research is that losing this inflammatory control can lead to chronic problems and eventually neurodegeneration
.

The main interest of this study is to understand the natural dynamics of the decline in lipid levels in the body during aging, a phenomenon that may be related to the brain's susceptibility to
cognitive impairment and neurodegenerative diseases.

Considering that the effects of lipoprotein A4 (LXA4) on the brain are not well understood, the study evaluated the possible effects of this biological activity on the brain environment and its activity, mainly related
to aging.
The scientists evaluated the molecule's presence
in mouse brains, in human nerve cells grown in the lab, and in cerebrospinal fluid (fluid) extracted from elderly patients with dementia and other neurodegenerative diseases.
This is the first study to show that LXA4 originated in the central nervous system, pointing to its presence in neurons and microglia (inflammatory cells) in
humans and mice.
Brain organoids developed in the lab, with biochemical features and structural organization similar to the brain of human embryos, have also been used to confirm this information
.

In addition, immunofluorescence (another technique that can assess the distribution of antigens in a sample) showed the presence of 5-lipoxygenase (5-LOX), an enzyme responsible for producing LXA4
in lab-developed brain organoids.
This dataset raises the possibility that neurons and microglia are involved in the transmission of LXA4 to the
human brain.

Controversial in the scientific literature, another research group linked
the presence of 5-LOX to synaptic dysfunction observed in animal models of Alzheimer's disease.
This study presents the opposite view and sheds light on the important aspect
of the brain that the lipoproteins produced by 5-LOX contribute to neuroprotection.

In mouse experiments, research focused on understanding the relationship between LXA4 and the aging process in animal models, hypothesizing that lowering levels of this substance weakens the body's defenses and leaves the brain vulnerable to neurodegeneration
.
LXA4 levels in plasma and brain of 12-month-old ("old") mice were observed to be lower
than in 3-month-old ("young adults") mice.
In old mice, decreased learning capacity and short-term memory loss were also demonstrated, suggesting that a decrease in LXA4 levels was accompanied by cognitive deficits
in older animals.

"This study made an important contribution
to determining the local presence of lipids in the central nervous system and the decline of lipid levels with age.
" This is a long-debated issue in
the scientific community.
Taking into account the findings of our group in a previous article, we were able to determine that this substance has a very important anti-inflammatory protective factor in the human brain and may prevent neurodegeneration in healthy aging individuals", mentioned
Dr.
Fabrício Pamplona, associate researcher at IDOR and UNILA and first author of the article.

The study also evaluated whether LXA4 injections had a protective effect
on memory alterations caused by inflammatory damage in mice.
The researchers observed that 7 days after LXA4 injection, cognitive stability and a decrease in inflammatory molecules appeared in the plasma of the rodents, which led the researchers to evaluate the relevance
of this lipin to patients with different diagnoses of nerve damage due to dementia or neurodegeneration.

In this experiment, we observed that the content of LXA4 in liquor decreased
as the patient aged and the severity of cognitive impairment occurred.
That is, the older the age, the greater the cognitive impairment and the lower the content of LXA4 in the
wine.
A decrease in LXA4 in cerebrospinal fluid has also been shown to be associated with the accumulation of β-amyloid (Aβ42), β-amyloid, one of
the neurotoxic markers of Alzheimer's disease.

An interesting novelty of this study is that LXA4 has an innovative mechanism involving enhancement
of the endocannabinoid system.
This system promotes balance in the body (called homeostasis), fine-grained control of neurotransmission, and influences a range of physiological processes, including appetite control, hormone release, cognition, pain, and inflammation
.
According to the group's line of research, LXA4 promotes neuroprotection when interacting with cb1-type cannabinoid receptors, resulting in better transmission of the endocannabinoid anandamide
.

"The CB1 receptor is the main key to the endocannabinoid system, which promotes the fine regulation
of the brain's neurotransmission system.
Lipids are known to promote the activation of the endocannabinoid system, and as we have already described in another study, the information produced and released by these molecules by immune cells (microglia) in the brain allows us to place their role in the context
of the interaction between the central nervous system and the immune system.
This regulation is another key role of the endocannabinoid system, suggesting that inflammation balance is critical to our brain health, especially during the aging process," said
Dr.
Pamplona.

Therefore, LXA4 will be a natural substance with dual anti-inflammatory and protective effects, and its decline with age will cause the brain to become "vulnerable"
to neurodegeneration.
The findings suggest that preventing LXA4 reduction can maintain brain environmental and cognitive health, and is also an important finding
for future treatments for neurodegenerative diseases.
The authors report that further research is needed to elucidate the mechanism of LXA4 activation and to evaluate how stimulating the production of the molecule can effectively slow cognitive decline
in older adults.