In a series of groundbreaking experiments involving lab-grown brain cells and mouse models, researchers at Johns Hopkins Medicine have unveiled a fascinating discovery concerning a cell surface protein known as Lag3. Not only does Lag3 serve as a biological target for FDA-approved drugs that bolster the immune system's ability to combat cancer, but it also emerges as a potential target for a drug designed to eliminate “misfolded” Tau proteins implicated in Alzheimer's disease.
Lag3, present on the surface of various cell types, including neurons in the brain, typically acts as a shield against immune system attacks. It has recently become a focus in cancer treatment, with an FDA-approved drug designed to heighten the susceptibility of melanoma to immune system assaults.
The latest findings, detailed in a publication in Advanced Science on February 7, shed light on Lag3's affinity for binding and spreading misfolded or aberrant Tau proteins, which are notorious contributors to Alzheimer's disease progression.
Ordinarily, Tau proteins play a crucial role in stabilizing the cellular scaffolding structure of microtubules. However, in Alzheimer's disease, these proteins detach from their structural roles, undergo misfolding, aggregate, and accumulate excessively within neurons, fueling disease progression.
The link between Lag3 and Tau proteins surfaced as the Johns Hopkins scientists, led by Dr. Xiaobo Mao, Associate Professor of Neurology at the Johns Hopkins University School of Medicine and member of the Institute for Cell Engineering, previously identified Lag3's binding to alpha-synuclein proteins, which are implicated in the neurodegeneration seen in Parkinson's disease.
In the current study utilizing lab-grown brain cells, researchers observed Lag3 binding to a pathogenic form of Tau protein circulating near neurons, subsequently engulfing the protein.
To explore the repercussions of Lag3 absence in neurons, scientists genetically engineered mice deficient in Lag3. Notably, these mice exhibited reduced transport of tangled Tau proteins into neurons.
In a pivotal step, researchers administered antibody drugs targeting Lag3 to mice with active Lag3 proteins. Encouragingly, this intervention resulted in diminished spread of Tau proteins in neurons and a reduction in behavioral deficits, including improved sociability, in the treated animals.
Dr. Ramhari Kumbhar, co-first author and research associate at the Johns Hopkins University School of Medicine, expressed optimism about the implications of these findings. He highlighted the potential of repurposing FDA-approved Lag3 antibodies intended for melanoma treatment to counter Alzheimer's disease progression by disrupting Lag3's propagation of toxic Tau proteins.
Dr. Mao reiterated the team's commitment to further investigating the therapeutic potential of Lag3 antibody drugs in Alzheimer's disease. This pioneering research not only unveils novel mechanisms underlying neurodegeneration but also holds promise for the development of targeted therapies to combat Alzheimer's disease and related conditions.
Source: Johns Hopkins University