The critical involvement of Tau in the heme-mediated neurocognitive responses in SCD mice. (A-B) Representative photomicrograph and relative fluorescence intensity for the expression of pTau in the isolated cerebral microvessels from vehicle (SS) and heme (SSH) injected SCD mice showing coexpression of pTau and aquaporin 4 (AQP4), marker for astrocytes adjacent to cerebral microvascular endothelium (original magnification ×20). (C-D) Representative photomicrograph and fluorescence intensity quantitation showing expression of pTau in heme-induced SS mice associated with GFAP⁺ reactive astrocytes. Arrows indicate coexpression of GFAP and pTau in some astrocytes (original magnification ×20). (n = 6; M, 3; F, 3). (E-G) Sickle bone marrow chimera mice with (SS^Tau+/+) or without (SS^Tau˗/˗) Tau deficiency in nonhematopoietic tissues, and control (AA) bone marrow transplanted Tau^+/+ mice (AA^Tau+/+) were challenged with heme and tested for neuroaxonal damage. Representative images showing DTI scans and SMI32/MBP expression within the indicated regions of corpus callosum and external capsule (original magnification ×20) from heme injected SS^Tau+/+, SS^Tau˗/˗ and AA^Tau+/+ mice (E), quantitation of FA (F), and SMI32/MBP intensity (G) demonstrating reduced neuroaxonal damage in absence of Tau (n = 6; M, 3; F, 3). (H-I) Improved exploration time (H) and discrimination index (I) in SS^Tau˗/˗ mice compared to SS^Tau+/+ mice (n = 8; M, 3; F, 5) observed during NOR testing at baseline, day 7, and day 14 following heme challenge. Unpaired t test between the indicated experimental groups. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. M, male mice; F, female mice; ns, not significant.