Neurodegenerative diseases in general, and Alzheimer’s disease (AD) in particular, are associated with multiple factors that contribute to disease escalation. Using immunological and immunogenomic tools, we described how aging of the immune system affects manifestation and progression of neurodegenerative diseases, which led us to envision that boosting the immune system might help supporting the brain. We found that one way to achieve this effect is by modestly reducing the restraints that are imposed on the immune system by the inhibitory immune checkpoint PD-1/PD-L1 pathway. Using this approach facilitated mobilization of bone- marrow derived macrophages to the diseased brain in animal models of amyloidosis and tauopathy. Systemic blocking CCR2, the chemokine receptor for monocytes migration, abrogated the beneficial effect. Transcriptomic profile of the MDM, using single cell RNA Seq revealed that they express molecules associated with anti-inflammatory activity, and scavenger receptors that can uniquely remove the intermediate toxic forms of misfolded proteins, dead cells, and cell debris, and thereby rescue synapses and brain function. We further found that the treatment was also effective in Trem2-deficient 5xFAD mice, which exhibited improvement of cognitive performance, reduced inflammation, and reduction of the amyloid beta oligomers, though not the plaques. Overall, our results indicate that targeting systemic rather than brain- specific disease-escalating factors provides a potential multi-dimensional disease-modifying therapeutic for AD and dementia, regardless of the primary disease etiology.
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