Abstract
Dear Editor:
In a recent commentary published in Bioelectricity, we highlighted the apparent two-way inverse association between the occurrences of cancer and degenerative brain disease/dementia in humans. 1 The impact of the brain on cancer is conceivable since tumors can be innervated and/or cancer cells possess receptors that can be acted upon by neurotransmitters arriving through the circulation. In contrast, the signaling basis of the reverse interaction (cancer to brain) has been more elusive. In a more recent article, Li et al. 2 have shown that a key molecule in that pathway is cystatin C (Cyst-C). The work involved a genetic mouse model of Alzheimer’s disease (AD) with allografted tumors (several types) extensively. From proteomic analysis and RNA-sequence profiling, Cyst-C was identified systematically as the key secretagogue released from the peripheral tumor cells. Importantly, Cyst-C was shown to cross the blood–brain barrier and, within the brain, bind to amyloid oligomers. The binding activated “triggering receptor expressed on myeloid cells 2” (TREM2) in microglia, leading the latter to degrade the pre-existing amyloid plaques by phagocytosis (protein–protein interaction between Cyst-C and β-amyloid). The specificity of these effects of Cyst-C was confirmed by cell-type-specific deletion or mutation of TREM2 or Cyst-C in microglia. The reduction in amyloid plaque burden resulted in a rescue of cognition, as expected.
As we speculated earlier, this is another facet of the burgeoning field of cancer neuroscience, and there are other candidate proteins, like PIN1. 3 Also, since AD proteins can generate electrophysiological activity, 4 it will be interesting to investigate the bioelectricity of these interactions.
Assuming that the current results can be translated to humans, this approach represents a significant conceptual advance with the ultimate promise of a clinical opportunity for precision-targeted AD therapy.