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Anti-Alzheimer’s Protein Complex Identified

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A new mouse study highlights the proteins responsible for LC3-associated endocytosis (LANDO), an autophagy process that is involved in degrading β-amyloid, the principal substance associated with Alzheimer’s disease.

Proteostasis

Proteins in the human brain can form misfolded, non-functional, and toxic clumps known as aggregates. Preventing these aggregates from forming, and removing them when they do, is a natural function of the human body, and it is known as proteostasis. However, as we age, this function degrades, and loss of proteostasis is one of the hallmarks of aging. The resulting accumulation of aggregates leads to several deadly diseases, one of which is Alzheimer’s.

Autophagy

As part of maintaining proteostasis, our cells consume unwanted proteins in a process called autophagy. In this particular case, specific receptors on specialized immune cells called microglia attach themselves to β-amyloid, bringing it into the cell and readying it for digestion. From there, this neurotoxic aggregate is brought to the lysosome, the specific cellular organelle that is responsible for autophagy. Under normal circumstances, the lysosome destroys the aggregate, the receptors are recycled back to the surface of the cell, and things continue as normal.



However, our cells can only consume toxins if their lysosomes have the correct machinery with which to do so. Macrophages, for example, attempt to consume cholesterol from our arteries, but as they are unable to digest this material, they become foam cells, compounding the problem instead of fixing it, which is why destroying this cholesterol is a project of the SENS Research Foundation.

LANDO

This study shows that our microglia require LANDO to effectively process β-amyloid. In the absence of LANDO, β-amyloid receptors are not recycled properly, thus preventing the uptake of fresh β-amyloid. This impairs proteostasis, allowing the toxic substance to accumulate and potentially leading to Alzheimer’s disease.

Summary

The expression of some proteins in the autophagy pathway declines with age, which may impact neurodegeneration in diseases, including Alzheimer’s Disease. We have identified a novel non-canonical function of several autophagy proteins in the conjugation of LC3 to Rab5 +, clathrin + endosomes containing β-amyloid in a process of LC3-associated endocytosis (LANDO). We found that LANDO in microglia is a critical regulator of immune-mediated aggregate removal and microglial activation in a murine model of AD. Mice lacking LANDO but not canonical autophagy in the myeloid compartment or specifically in microglia have a robust increase in pro-inflammatory cytokine production in the hippocampus and increased levels of neurotoxic β-amyloid. This inflammation and β-amyloid deposition were associated with reactive microgliosis and tau hyperphosphorylation. LANDO-deficient AD mice displayed accelerated neurodegeneration, impaired neuronal signaling, and memory deficits. Our data support a protective role for LANDO in microglia in neurodegenerative pathologies resulting from β-amyloid deposition.

Conclusion



While this is a mouse study, and the exact reason for the decrease in LANDO is not yet understood, this represents a significant step forward in our understanding of Alzheimer’s and what may cause microglia to stop processing the deadly aggregate associated with it. More research will be required to find ways to restore this process in microglia and thus potentially ameliorate Alzheimer’s.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
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