An immune process implicated earlier this year in schizophrenia may also cause the devastating brain damage of Alzheimer’s disease, a surprising convergence that suggests the body’s defense system is responsible for two of the cruelest brain disorders.
The new findings, reported Thursday in Science, show how synapses — the connections between neurons in the brain — get engulfed and devoured by immune cells. Loss of synapses, especially in the hippocampus and frontal cortex, causes the memory and cognitive crash that marks Alzheimer’s progression.
Since efforts to develop drugs for Alzheimer’s have been an almost unbroken litany of failure, the results suggest an approach strikingly different from the one that has ruled for three decades.
And although any new therapies are years away — the study was in mice, which are often poor predictors of what will work in people — two upstart companies are racing to develop Alzheimer’s drugs that target the immune system.
“I think this is a great discovery and will spark a lot of interest,” said Joseph Rogers, who in the 1980s helped originate the idea that the immune system is involved in neurodegenerative diseases. Rogers, now acting president and executive director of special projects at SRI International, a nonprofit research center in Silicon Valley, was not involved in the new study.
The discovery that the immune system destroys synapses grew from one that neurobiologist Beth Stevens helped make as a postdoctoral fellow in Ben Barres’s lab at Stanford University nearly a decade ago: Working with mice, Stevens and her colleagues showed in 2007 that immune molecules act as pruning shears in the developing brain, trimming unneeded synapses.
“We thought the same pruning pathway” — which is healthy in young brains — “might be relevant to neurodegenerative diseases,” said Stevens, now at Boston Children’s Hospital.
Using mouse models again, this time with a rodent version of of Alzheimer’s disease, Stevens and her team aimed a super-resolution microscope at the animals’ brains. Synapses, they saw, start disintegrating well before the appearance of plaques, the sticky clumps around neurons that have been the target of many drug development efforts. The vanishing synapses were covered with high levels of a molecule called C1q.
In the early developing brain, this molecule acts like one of those tags arborists slap on trees marked for destruction: it causes redundant synapses to be eliminated. But now C1q was marking synapses that the brain very much needed.
When the scientists disabled C1q in various ways, the mice’s synapses survived; no C1q, no synapse loss. “If you block this process you block the degeneration of synapses,” said Barres, a coauthor of the new study.
If an antibody or targeted genetic therapy such as CRISPR could do that in people, Barres added, it might stop synapse destruction in the earliest stages of Alzheimer’s, halting progression of the disease. That is also the hope raised by Stevens’ January study in the journal Nature, which implicated overpruning, and some of the same molecules, in schizophrenia.
The new study does not overturn the controversial “amyloid model” of Alzheimer’s. It found that a molecule called amyloid-beta, the building block of plaques, seems to elevate brain levels of C1q, setting the destructive cascade in motion. But efforts to treat Alzheimer’s by targeting amyloid directly have failed.
The findings raise hopes that aiming, instead, at the immune cells that destroy synapses might be more effective. “But we have to keep in mind that these are mouse models,” Stevens said, and so might not be perfect mimics of human disease. For one thing, no one knows if adult brains need C1q.
Nonetheless, two San Francisco-based biotech firms are now working on ways to treat Alzheimer’s via this immune pathway.
Annexon Biosciences, which Barres cofounded in 2011 and which counts Stevens on its scientific advisory board, is testing a human form of the antibody that blocks C1q, called ANX-005. And a company called Alector, which formed two years later, is working on similar immune approaches; Barres sits on its advisory board.
One reason the discovery is generating excitement is that it fits with the idea that Alzheimer’s is a result of inflammation in the brain.
The “neuroinflammation” hypothesis has come and gone, but it’s making a comeback. Next month, the Alzheimer’s Association will announce the recipients of up to $4 million each in funding for neuroinflammation-related research projects intended to lead to therapies.
Rogers suspects that’s only the start. “This paper,” he said, “will stimulate a lot of interest in studying the role of neuroinflammation in Alzheimer’s and finding [therapies] that target it.”