Vesicles That Trap Amyloid Appear to Contribute to Alzheimer’s

Summary: Reducing the production of exosomes may help slow the progression of Alzheimer’s disease.

Source: Medical College of Georgia at Augusta University.

Vesicles, fluid-filled sacs that brain cells make to trap amyloid, a hallmark of Alzheimer’s, appear to also contribute to the disease, scientists report.

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, scientists at the Medical College of Georgia at Augusta University report in The Journal of Neuroscience.

When confronted with amyloid, astrocytes, plentiful brain cells that support neurons, start making exosomes, to capture and neutralize it, said Dr. Erhard Bieberich, neuroscientist in the MCG Department of Neuroscience and Regenerative Medicine and the study’s corresponding author.

“If you swarm astrocytes with amyloid, you trigger an aggressive response,” he said. Happy astrocytes, on the other hand, don’t make exosomes.

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, Bieberich said.

MCG 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 known for its skin-softening ability.

The MCG 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, said Bieberich, noting that Alzheimer’s tends to be more aggressive in women. His 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.

His 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, Bieberich said. Current strategies to prevent plaque formation, have been unsuccessful, the researchers write.

“We show clearly that sphingomyelinase is causative here in making ceramide, making exosomes and in making plaques,” Bieberich said. He and his teams already are testing different drugs given to patients for reasons other than Alzheimer’s that may also inhibit sphingomyelinase and ultimately ceramide and exosome production.

Image shows an Alzheimer's brain slice.
Scientists found exosomes made by astrocytes accelerated the formation of beta amyloid and blocked its clearance in their animal model of Alzheimer’s. NeuroscienceNews.com image is for illustrative purposes only.

Inside the brain, ceramide is an important component of the cell membrane, but too much starts collecting in the exosomes, combining with the amyloid to form a disruptive and eventually deadly aggregate. In fact, MCG scientists could see the ceramide and amyloid clustered together in the brains of mice without sphingomyelinase suppression, further implicating a close association.

In a scenario that seems to go full circle, Bieberich has mounting evidence that in Alzheimer’s, there is a shorter, “bad” form of ceramide coating the antennae of astrocytes. Normally, antennae help astrocytes focus on taking care of neurons. But the shorter version that he believes contributes to disease has astrocytes giving up their caretaker role, spending their energy on themselves and starting to divide.

Bieberich and his team already are looking for other exosome triggers such as inflammation-producing immune cells called cytokines as well as physical trauma. Ceramide levels have been proposed as an early Alzheimer’s biomarker as has evidence of amyloid-positive exosomes in the blood.

About this Alzheimer’s disease research article

Funding: The research was funded by the National Institutes of Health.

Source: Toni Baker – Medical College of Georgia at Augusta University
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Neutral Sphingomyelinase-2 Deficiency Ameliorates Alzheimer’s Disease Pathology and Improves Cognition in the 5XFAD Mouse” by Michael B. Dinkins, John Enasko, Caterina Hernandez, Guanghu Wang, Jina Kong, Inas Helwa, Yutao Liu, Alvin V. Terry, Jr., and Erhard Bieberich in Journal of Neuroscience. Published online August 17 2016 doi:10.1523/JNEUROSCI.1429-16.2016

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]Medical College of Georgia at Augusta University. “Vesicles That Trap Amyloid Appear to Contribute to Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 29 August 2016.
<https://neurosciencenews.com/alzheimers-amyloid-vesicles-4928/>.[/cbtab][cbtab title=”APA”]Medical College of Georgia at Augusta University. (2016, August 29). Vesicles That Trap Amyloid Appear to Contribute to Alzheimer’s. NeuroscienceNew. Retrieved August 29, 2016 from https://neurosciencenews.com/alzheimers-amyloid-vesicles-4928/[/cbtab][cbtab title=”Chicago”]Medical College of Georgia at Augusta University. “Vesicles That Trap Amyloid Appear to Contribute to Alzheimer’s.” https://neurosciencenews.com/alzheimers-amyloid-vesicles-4928/ (accessed August 29, 2016).[/cbtab][/cbtabs]


Abstract

Neutral Sphingomyelinase-2 Deficiency Ameliorates Alzheimer’s Disease Pathology and Improves Cognition in the 5XFAD Mouse

Recent evidence implicates exosomes in the aggregation of Aβ and spreading of tau in Alzheimer’s disease. In neural cells, exosome formation can be blocked by inhibition or silencing of neutral sphingomyelinase-2 (nSMase2). We generated genetically nSMase2-deficient 5XFAD mice (fro;5XFAD) to assess AD-related pathology in a mouse model with consistently reduced ceramide generation. We conducted in vitro assays to assess Aβ42 aggregation and glial clearance with and without exosomes isolated by ultracentrifugation and determined exosome-induced amyloid aggregation by particle counting. We analyzed brain exosome content, amyloid plaque formation, neuronal degeneration, sphingolipid, Aβ42 and phospho-tau levels, and memory-related behaviors in 5XFAD versus fro;5XFAD mice using contextual and cued fear conditioning. Astrocyte-derived exosomes accelerated aggregation of Aβ42 and blocked glial clearance of Aβ42 in vitro. Aβ42 aggregates were colocalized with extracellular ceramide in vitro using a bifunctional ceramide analog preloaded into exosomes and in vivo using anticeramide IgG, implicating ceramide-enriched exosomes in plaque formation. Compared with 5XFAD mice, the fro;5XFAD mice had reduced brain exosomes, ceramide levels, serum anticeramide IgG, glial activation, total Aβ42 and plaque burden, tau phosphorylation, and improved cognition in a fear-conditioned learning task. Ceramide-enriched exosomes appear to exacerbate AD-related brain pathology by promoting the aggregation of Aβ. Reduction of exosome secretion by nSMase2 loss of function improves pathology and cognition in the 5XFAD mouse model.

SIGNIFICANCE STATEMENT We present for the first time evidence, using Alzheimer’s disease (AD) model mice deficient in neural exosome secretion due to lack of neutral sphingomyelinase-2 function, that ceramide-enriched exosomes exacerbate AD-related pathologies and cognitive deficits. Our results provide rationale to pursue a means of inhibiting exosome secretion as a potential therapy for individuals at risk for developing AD.

“Neutral Sphingomyelinase-2 Deficiency Ameliorates Alzheimer’s Disease Pathology and Improves Cognition in the 5XFAD Mouse” by Michael B. Dinkins, John Enasko, Caterina Hernandez, Guanghu Wang, Jina Kong, Inas Helwa, Yutao Liu, Alvin V. Terry, Jr., and Erhard Bieberich in Journal of Neuroscience. Published online August 17 2016 doi:10.1523/JNEUROSCI.1429-16.2016

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