Light clears toxic protein in mice with Alzheimer’s

The brain’s cleanup crew can be kicked into action to mop up harmful proteins linked to Alzheimer’s disease, a new mouse study shows, with nothing but a flickering light.

Researchers in the US, led by Li-Huei Tsai, a neuroscientist from the Massachusetts Institute of Technology, used light to induce a particular pattern of brain waves in mice that develop Alzheimer’s disease. They saw microglia – immune cells in the brain that consume waste and debris – more than doubled in number and ramped up their consumption of beta-amyloid, a protein associated with Alzheimer’s disease.

The work was published in Nature.

Alzheimer’s disease – the most common form of dementia – affects 46 million people worldwide, and is projected to cost US$2 trillion globally by 2030. Symptoms include memory loss, cognitive difficulties and personality changes.

But under the skin, one of the main pathological hallmarks is globs of a protein called beta-amyloid peppered throughout the brain.

Beta-amyloid is found in normal, healthy brains in the interstitial fluid bathing the cells. Studies suggest it protects against microbial infections, for instance.

But when the protein aggregates to form plaques, they become toxic to surrounding cells. Neurons become sick, stop communicating with other cells and die. But this build-up begins before patients exhibit Alzheimer’s symptoms.

And exactly why beta-amyloid starts to clump is a mystery. In 2011, US researchers found neuronal activity at least partly drives the amount of beta amyloid in the local interstitial fluid.

Neurons don’t work alone – they form networks which oscillate at a range of frequencies. If they fire between 30 and 120 times each second (30 to 120 hertz), this puts them in the gamma waves range.

Gamma oscillations are weakened in patients with Alzheimer’s disease. Where a healthy brain might produce oscillations with high amplitude – that is, high peaks and deep troughs – an Alzheimer’s brain’s gamma waves are flatter.

But it’s unclear as to if these changes occur early in disease progression and how they affect disease development.

Tsai and her crew wanted to find out. They used a staple of Alzheimer’s research – mice with a genetic mutation that causes them to overproduce beta amyloid. Given time, the mice would eventually go on to develop plaques, but the researchers were interested in the early stages – when the mice had higher than normal levels of amyloid-beta proteins, but no plaques or memory and learning problems.

“Gamma waves [are] critical for multiple cognitive functions, such as perception, memory and attention, which are all impaired in Alzheimer’s disease,” Tsai says.

And even at these early stages, the gamma amplitude in a region of the hippocampus, the part of the brain responsible for learning and memory, was flatter than normal. Waves at 40 hertz were most affected.

This led to the question – could such changes to gamma waves play a role in the development of beta amyloid plaques?

To find out, the researchers used a technique known as optogenetics. Mouse brain cells were genetically engineered to fire if light of a certain colour was shone on them.

The implanted a fibre optic light source into the hippocampus of the mice and blasted them with 40-hertz light pulses for an hour.

The result? An almost 50% reduction in the levels of beta-amyloid when compared to untreated mice – thanks to the brain’s cleaner cells called microglia.

Microglia are found throughout the brain and spinal cord. Normally, they’re scavengers, cleaning up toxic material and cell debris. But in Alzheimer’s patients, they don’t work as well – and leak toxic molecules, which make neurons even sicker.

Tsai’s team found almost twice as many microglia in the brain of gamma-wave-treated Alzheimer’s mice than in untreated mice. Even more astoundingly, the microglia were bigger, detaining more beta amyloid.

Restoring normal gamma oscillations in Alzheimer’s mice, it seemed, caused genetic changes in microglia cells, prompting them to eat more beta amyloid.

To create a technique that didn’t involve sticking cables into the brains, the researchers devised a non-invasive flickering light method.

Just one hour of LED lights at flickering at 40 hertz, shone into the into the eyes of Alzheimer’s mice, halved beta amyloid in the brain’s primary visual cortex compared to counterparts kept in the dark. As in the optogenetics experiment, microglia became fatter and hungrier for the protein.

The researchers then tried their tactic on older mice that had already developed plaques.

Treating the mice with one hour of flickering every day for seven days, the load of harmful plaques within the brain of these mice reduced by about 60%.

Colin Masters, a neuroscientist from the University of Melbourne, Australia, who was not involved in the research, remarks that while the results obtained from the flickering light mechanism are “pretty amazing” and that “it’s very intriguing that the microglia got excited”.

But, he cautions, that “there’s no point in just activating [the] visual cortex, which is not really affected much in human Alzheimer’s disease”. Nor do the researchers address cognitive deficits.

Still, the researchers are hopeful their technique might be trialled in humans.

“Mouse vision is known to be not very good,” Tasi says. “It is possible that in other species – such as humans – with better vision, this kind of sensory stimulation could be even more effective.”

The Massachusetts Institute of Technology, which housed much of the research, licensed the technology to a startup company, which is currently communicating with the US Food and Drug Administration in the hope of carrying out human clinical trials as soon as possible.