LANDO Found to be Key to Microglial Clearance of Amyloid-β and Neuroinflammation

The consensus view on the progression of Alzheimer's disease is that it begins with rising levels of amyloid-β aggregates, misfolded proteins forming solid deposits to disrupt cellular behavior. This increase in amyloid-β might be due to persistent infection, as amyloid-β is an antimicrobial peptide, a part of the innate immune system. It might be due to failing drainage of cerebrospinal fluid, causing all molecular wastes to build up in the brain. There are other possibilities as well, such as progressive failure of the ability of immune cells to clear out amyloid-β.

In and of itself this rising level of amyloid-β seems to, at worst, cause mild cognitive impairment via dysfunction of neurons. Unfortunately it also causes microglia and other support cells to become dysfunctional and inflammatory. That in turn sets the stage for tau protein to become altered and form its own solid deposits. Tau aggregates are far worse than amyloid-β aggregates, and lead to widespread and severe cell dysfunction and death in the brain.

Even given the decades of failure in clearance of amyloid-β from the brain, primarily via immunotherapies, it still seems plausible that early enough intervention to reduce amyloid-β levels should prevent the development of Alzheimer's disease. Late intervention is simply too late - the disease mechanisms are chronic inflammation and tau aggregation by that time. A potentially promising new area of intervention is to prevent the impact of amyloid-β on microglia and other support cells from producing this chronic inflammation and tau aggregation. Promising results have been achieved in animal models via clearance of senescence microglia and astrocytes, reducing the level of inflammation and aggregated tau in the brain by removing these dysfunctional support cells from the picture.

Today's open access research takes a different approach to the same point of intervention. The authors have identified one of the critical proteins involved in the ability of microglia to ingest and break down amyloid-β. This offers the possibility of enhancing their ability to do so, and in turn reduce the fraction of microglia that become inflammatory and dysfunctional due to the presence of too much amyloid-β. Time will tell how well this works, but the evidence from other approaches to removing or replacing microglia in the aging brain suggests that this is worth the attempt.

Pathway discovered that prevents buildup of Alzheimer's protein

Researchers called the pathway LC3-associated endocytosis or LANDO. They found the pathway in microglial cells, the primary immune cells of the brain and central nervous system. However, preliminary evidence suggests LANDO is a fundamental process that functions in cells throughout the body. Investigators showed that LANDO protected against deposits of neurotoxic β-amyloid protein in mice. Activation of the pathway also guarded against toxic neuroinflammation and neurodegeneration, including memory problems.

β-amyloid protein accumulation in neurons is a hallmark of Alzheimer's. Scientists knew microglial cells take up β-amyloid proteins. Discovery of the LANDO pathway answers questions about what comes next. The researchers compared LANDO to the operator of an automatic carwash. In this case, the cars are the receptors on the microglial cells that bind to neurotoxic β-amyloid proteins and bring the protein into the car wash. And, just as cars return to the streets after the dirt is gone, when the β-amyloid is disposed of, the receptor returns to the microglial surface where it can pick up additional β-amyloid.

Several proteins are required for LANDO functioning. The proteins - Rubicon, Beclin 1, ATG5, and ATG7 - are better known for their roles in a related cell pathway used to recycle unneeded and unwanted cell components. These proteins decline with age as their expression decreases.

LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer's Disease

The expression of some proteins in the autophagy pathway declines with age, which may impact neurodegeneration in diseases, including Alzheimer's disease (AD). 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.

Comments

There's an ever-growing amount of variety in methods being developed to target the underlining age-related damage that causes Alzheimer's, and it's a reminder that, while yes, there's still plenty of rejuvenation research left to do, and it's important to avoid complacency because the research isn't going as quickly as the science would allow if given adequate funding, progress is still actually occurring. I know I'm preaching to the choir saying this, but I'm looking forward to seeing how effective Arethusta is. Does anyone here know of a rough estimate in which Leucadia Therapeutics will begin clinical trials?

Posted by: Quinn at July 5th, 2019 4:07 PM

There should seriously be a study on fasting's impact on MCI to ALzheimer conversion.. Not sure how this is gonna relate to defeating aging though

Posted by: Johannes Høher-Larsen at July 5th, 2019 4:16 PM

Given the massive cost of Alzheimer's to society, I find it a little mad that the SENS Research Foundation had to step in and find work on the intra cellular removal of tau.

At least Alzheimer's research funding in the US has now belatedly increased to 2 billion dollars per annum.

Posted by: jimofoz at July 7th, 2019 5:03 AM

@Reason: Off topic, but will it be possible to produce meat low in methionine?

Posted by: Norse at July 7th, 2019 11:31 AM

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