Vesicles and Amyloid in Alzheimer's Disease

Researchers have uncovered another way in which growing amounts of amyloid, aggregates of a misfolded protein, can cause dysfunctional cellular behavior in the brain. As presented, this is actually a good example of the way in which research to explore exactly how a disease state progresses tends to focus on the novel mechanisms rather than the known root causes, to the detriment of building better therapies. The right approach is to tackle the root causes, and with greater support for that approach provided by the new knowledge as to why those root causes are in fact damaging. Instead research institutions chase after ways to manipulate newly discovered secondary effects because they are novel and therefore open to patent protection or other forms of ownership:

Vesicles, fluid-filled sacs that brain cells make to trap amyloid, a hallmark of Alzheimer's, appear to also contribute to the disease. Reducing the production of these vesicles, called exosomes, could help reduce the amount of amyloid and lipid that accumulates, slow disease progression and help protect cognition. When confronted with amyloid, astrocytes, plentiful brain cells that support neurons, start making exosomes, to capture and neutralize it. Not unlike a landfill, the real problems begin when the biological sacs get piled too high. In such volume and close proximity to neurons, exosomes begin to interfere with communication and nutrition, neurons stop functioning well and eventually begin to die, a scenario that fits with disease progression.

Scientists followed the process in an animal model with several genetic mutations found in types of Alzheimer's that tend to run in families and make brain plaques early in life. One mouse group also was genetically programmed to make a nonfunctional form of the enzyme neutral sphingomyelinase-2. Amyloid also activates this enzyme, which converts another lipid, called sphingomyelin, into ceramide, a component of the brain cell membrane known to be significantly elevated in Alzheimer's. In fact, with disease, the brain has two to three times more of the lipid. The scientists found exosomes made by astrocytes accelerated the formation of beta amyloid and blocked its clearance in their animal model of Alzheimer's. Male mice, which were also sphingomyelinase-deficient, developed fewer plaques and exosomes, produced less ceramide and performed better in cognitive testing. For reasons that are unclear, female mice did not reap similar benefits; Alzheimer's tends to be more aggressive in women. Earlier work has shown that female mice have higher levels of antibodies in response to the elevated ceramide levels that further contribute to the disease.

The new work is the first evidence that mice whose brain cells don't make as many exosomes are somewhat protected from the excessive plaque accumulation that is the hallmark of Alzheimer's. It is also an indicator that drugs that inhibit exosome secretion may be an effective Alzheimer's therapy. The team is already testing different drugs given to patients for reasons other than Alzheimer's that may also inhibit sphingomyelinase and ultimately ceramide and exosome production.



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