Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease

Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-beta protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE(10) model) substantially diminished Alzheimer's-like disease in double-transgenic APP(SWE)/PS1(Delta E9) (AD(+)) mice. hi this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE(10) macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD(+) mice: (i) ACE(10)/GFP(+) bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115(+)-ACE(10/)(GFP)(+ )monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE(10)-macrophage phenotype(s) in response to amyloid-beta(1-)(42) fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE(10) as compared to wild-type monocytes (similar to 3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-beta(1-)(42), vascular and parenchymal amyloid-beta deposits, and astrocytosis (31%, 47-80%, and 33%, respectively; P < 0.05-0.0001). ACE(10) macrophages surrounded brain and retinal amyloid-beta plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and similar to 60% lower tumour necrosis factor-alpha (P < 0.05). Importantly, blood enrichment with CD115(+)-ACE(10 )monocytes in symptomatic AD(+) mice resulted in pronounced synaptic and cognitive preservation (P < 0.05-0.001). In vitro analysis of macrophage response to well-defined amyloid-beta(1-42) conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-1 2 species by ACE(10) macrophages. They exhibited 2-5-fold increased surface binding to amyloid-beta conformers as well as substantially more effective amyloid-beta(1-)(42) uptake, at least 8-fold higher than those of wild-type macrophages (P < 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P < 0.05-0.0001), endosomal processing (P < 0.05-0.0001), and similar to 80% increased extracellular degradation of amyloid-beta(1-42) (P < 0.001). Beneficial ACE(10) phenotype was reversed by the angiotensinconverting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Further, ACE(10) macrophages presented distinct anti-inflammatory (low inducible nitric oxide synthase and lower tumour necrosis factoret), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimer's-related amyloid-beta(1-42) oligomers. Overall, we provide the first evidence for therapeutic roles of angiotensin-converting enzyme-overexpressing macrophages in preserving synapses and cognition, attenuating neuropathology and neuroinflammation, and enhancing resistance to defined pathognomonic amyloid-beta forms.