17 May 2019

If using flashing lights to treat Alzheimer’s disease sounds like science fiction, then brace yourself, because new data strengthen the case for this idea. Previously, Li-Huei Tsai and colleagues at MIT had reported that a treatment consisting of patterned light pulses boosted gamma waves and diminished plaque load in the visual cortex of an AD mouse. Now, Tsai and colleagues follow this up with studies in additional models of neurodegeneration. The treatment strengthened synaptic function, preserved neurons, and improved learning and memory, the scientists reported on May 2 in Neuron online. “We think this approach could delay or ameliorate neurodegeneration,” Tsai wrote to Alzforum.

Treatment with pulsing lights preserves neurons in two AD models.

Light curbed inflammation and microgliosis.

It also strengthened synaptic signaling, learning, and memory.

“This is again brilliant work from the Tsai lab,” commented Marc Busche at University College London. “The results provide further evidence that neural circuit activity is not only related to symptoms, but directly contributes to disease progression. I believe these data provide additional preclinical support for a gamma stimulation therapy in patients with Alzheimer’s disease and related neurodegenerative disorders.”

In the earlier study, Tsai and colleagues exposed 5XFAD mice to an LED light flashing at 40 Hz. This cut Aβ production in visual cortex by more than half, and plaque load by two-thirds. Amyloid cleanup appeared to be due, at least in part, to more active phagocytosis by microglia, which assumed a more globular shape and internalized more Aβ during light treatment. Likewise, in P301S (PS19) tau mice, 40 Hz light pulses activated microglia, and phosphorylated tau dropped nearly in half (Dec 2016 news).

Neuronal Preservation. The inducible p25 model of neurodegeneration (middle) loses gray matter, but gamma entrainment (right) preserves cortical thickness at nearly wild-type levels (left). [Courtesy of Neuron, Adaikkan et al.]

In the new study, the authors asked whether light treatment, which they dubbed gamma entrainment using sensory stimuli (GENUS), would slow neurodegeneration. First author Chinnakkaruppan Adaikkan initially tested GENUS in wild-type mice, finding that it amped up gamma oscillations not just in visual cortex, but also in prefrontal and somatosensory cortex and hippocampal CA1. In addition, neuronal activity between visual cortex and these other regions became more synchronized. The finding suggested that GENUS could have widespread effects on the brain, including in areas most affected by AD.

Next, the authors exposed 7.5-month-old PS19 tau mice to a daily hour of GENUS for 22 days. At this age, neurons in visual cortex and CA1 are starting to die. GENUS prevented this, maintaining neurons at wild-type levels. In a second neurodegeneration model, induction of p25 leads to rapid tau phosphorylation and accumulation of tangles, as well as plaque formation and neuronal death (Jun 2004 news). In these mice, researchers began GENUS at the same time as they induced p25. Six weeks later, treated mice had as many neurons and nearly as thick a cortex as controls, while untreated mice had lost about 20 percent of their neurons and gray matter (see image above).

As in the 5XFAD mice, some of the benefits may be due to dampened inflammation. In both models, GENUS partially suppressed microgliosis and expression of inflammatory genes, although inflammation was still up relative to age-matched wild-type controls (see image below).

Calming Inflammation. Microglia (green) activate in the inducible p25 model of neurodegeneration (middle), but gamma entrainment (right) lessens this, keeping microglia in between the homeostatic (left) and untreated state. [Courtesy of Neuron, Adaikkan et al.]

GENUS also appeared to have direct effects on neurons and synapses. During neurodegeneration, expression wanes for neuronal synaptic transmission and vesicle transport genes, but gamma entrainment keeps it at wild-type levels. In addition, in neurodegeneration synaptic transmission proteins become more phosphorylated; GENUS reversed this, too. With GENUS, dendrites sported more mushroom spines, which are part and parcel of excitatory synaptic signaling. Finally, the treatment boosted expression of proteins that protect DNA, and reduced markers of DNA damage in neurons.

In line with these synaptic effects, GENUS enhanced learning and memory. Treated CK-p25 mice learned and remembered the location of a hidden platform in the Morris water maze better than did untreated mice. Treated PS19 mice also learned faster than untreated, but had only slight improvements in memory.

Intriguingly, perhaps, aged wild-type mice exposed to GENUS learned faster than age-matched controls. Their synaptic proteins were less phosphorylated, hinting that their synaptic function might be restored. To Tsai, the data suggest that gamma entrainment might counteract some of the cognitive decline of normal aging.

While the findings imply that gamma entrainment can stave off neurodegeneration, it remains to be seen whether it helps at more advanced stages. Tsai’s lab is testing this in older mice. Meanwhile, a start-up she co-founded, Cognito Therapeutics, is exploring safety and tolerability of the therapy in a Phase 1 trial of 60 people with mild AD or mild cognitive impairment due to AD, and dosing in 20 more.—Madolyn Bowman Rogers