Neurodegeneration as a Breakdown of Brain-Immune Crosstalk: A Cell Review Identifies Three Mechanisms and Proposes Treating Parkinson's and ALS with Cell Therapies Borrowed from Oncology
Neurodegeneration as a Breakdown of Brain-Immune Crosstalk: A Cell Review Identifies Three Mechanisms and Proposes Treating Parkinson's and ALS with Cell Therapies Borrowed from Oncology
Four researchers have synthesized recent years of evidence in Cell: immune cells actively participate in neurodegenerative disease, sometimes protecting the brain and sometimes amplifying the damage. The authors identify three mechanisms behind this breakdown and show that already approved Alzheimer's drugs act through the brain's immune system.
The brain was long considered a zone inaccessible to the immune system: the blood-brain barrier kept lymphocytes and other immune cells on the outside. In 2015, Jonathan Kipnis's laboratory discovered lymphatic vessels in the meninges, the same kind of channels through which immune cells circulate in the rest of the body. It turned out that the brain drains much like any other tissue: the immune system has a physical route in, but these vessels had simply gone unnoticed.
Since then, a scattered list of findings has accumulated: one laboratory catches immune cells in the meninges, another finds them in brain tissue in a specific disease. Bennett, Hong, Jiang, and Marazzi brought these findings into a single framework in a paper published in Cell on August 20:
Disrupted neuroimmune interaction is not a consequence of neurodegeneration but its constant co-driver, a co-cause of the disease.
The authors divide the breakdown into three mechanisms by the location of the signal: T cells in the peripheral body, microglia in the brain, and cellular memory. The location of the signal is what determines the future point of therapeutic intervention.
The first mechanism involves immune cells trained outside the brain that attack it from the periphery. In Parkinson's disease, blood T cells recognize alpha-synuclein, the very protein that forms toxic aggregates in the brain. In amyotrophic lateral sclerosis (ALS), TDP-43 exits the nucleus of the nerve cell and exposes regions that T cells never normally encounter, causing them to treat the protein as foreign. In mouse models of Parkinson's disease, T cells are primed in the gut: local macrophages engulf alpha-synuclein aggregates and teach T cells to recognize the protein, after which the T cells migrate to the brain. In a subset of patients, protein aggregates appear in the gut before the brain is affected, and chronic constipation is one of the earliest signs of the disease, preceding tremor.
The second mechanism involves microglia, the brain's resident immune cells. In one context, microglia help clear protein aggregates; in another, they trigger aggregate formation themselves and destroy synaptic connections between neurons.
The third mechanism is cellular memory: after inflammation or stress, immune and nerve cells change their set of active genes for extended periods, locking in a pathological state without any alteration to the DNA itself.
This framework also explains how approved drugs work: lecanemab and donanemab, commonly viewed as simple amyloid plaque dissolvers, in fact signal microglia to engulf the plaques. Going further, the authors propose adapting an oncology technology for the brain: the patient's own T cells, genetically reprogrammed to attack a specific target, directed against known protein targets in Parkinson's disease and ALS. Kipnis's laboratory, which discovered the meningeal lymphatic vessels in 2015, is already testing such cells in Alzheimer's disease: in mice, they markedly reduced the number of plaques and inflammation.
The immune response in the brain is context-dependent: T cells kill neurons in one model and protect them in another. Treatment must therefore hit precisely the right moment and the right signal, because a broad intervention risks disrupting both scenarios at once.