Researchers were able to restore the function of neurons linked to cognitive function and information processing in mice that mimic key features of Alzheimer's disease, showing early promise for the development of a similar targeted therapy in humans.
The findings were published today in Neuron .
At the core of the research is the relationship between gamma oscillations and parvalbumin interneurons in the brain. Gamma oscillations are rapid electrical rhythms that occur when an individual is learning, forming memories, and processing information. Parvalbumin interneurons, also referred to as PV cells, are primarily responsible for generating these gamma oscillations.
"Gamma oscillations are disrupted in the brain of Alzheimer's patients," said first author Keran Ma, PhD , assistant professor in the Department of Neurobiology and Anatomy at McGovern Medical School at UTHealth Houston. "Even before patients are diagnosed with Alzheimer's disease, when they start to show some symptoms—for example, mild cognitive impairment—changes in gamma oscillations are already present. Early on in Alzheimer's disease, the disrupted gamma oscillations are accompanied by progressive PV cell dysfunction."
Ma and her team found that not only could PV function be restored by giving the mice a sodium channel subunit, but that PV cells do not all work in coordination as previously thought.
"PV interneurons are not all activated at the same time uniformly and fire in synchrony during gamma oscillations" Ma said. "They actually get recruited sequentially. There's a pattern of recruitment. There's a timing in how active these cells are to initiate the onset of gamma oscillations and to sustain gamma oscillations."
Alzheimer's disease is a human condition that is not found in mice. Ma and her team used mice that were given the human version of an amyloid protein that led to amyloid plaque buildup in the mice's brains to replicate what is seen in humans with the disease.
"We found that the pattern of PV cell recruitment was restored after PV cell function was enhanced by a sodium channel subunit, and the mice showed improved gamma oscillations," Ma said. "This is proof of principle that we can manipulate these PV interneurons to increase gamma oscillations."
Authors from the Gladstone Institute of Neurological Disease are Kyerl Park, PhD; Patrick Honma, PhD; Erica Brady, PhD; Yuechen Qiu, MS; Katerina Akassoglou, PhD; Jorge J. Palop, PhD; and Yutong Zhang, research associate.
Authors from the Allen Institute for Brain Science include Jonathan T. Ting, PhD; Boaz P. Levi, PhD; and Ximena Opitz-Araya, research associate.
