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Reelin-COLBOS knock-in mice express an H3448R (histidine to arginine) amino acid substitution in the Reln (reelin) locus. The H3448R mutation models the human H3447R variant, and serves as a gain of function mutation that provides resistance to Autosomal dominant Alzheimer's disease (ADAD). This strain may be useful for studies of Alzheimer's disease.
Reln encodes for the glycoprotein, reelin, that is secreted by specific cell types in the developing brain. Reelin has been implicated in cell-cell interactions to activate neuronal migration and cortical laminar formation.
Reelin-COLBOS (COLBOS – Columbia-Boston biomarker research study) knock-in mice express an H3448R (histidine to arginine) amino acid substitution in the C-terminal of Reln. The mutation corresponds to a rare human H3447R variant found in a male patient with Autosomal dominant Alzheimer’s disease (ADAD). The patient, although carrying the PSEN1-E280A mutation, had a limited entorhinal Tau tangle burden. Mice homozygous for the mutation are viable and fertile, with no overt phenotype. The mutation creates a gain of function hypermorph that has enhanced phosphorylation of Dab1 in homozygous males; activation of DAB1 reduces human Tau phosphorylation. Reelin-COLBOS homozygous males also have a mild increase in cerebellar neurons. When combined with a human tauopathy mouse model (Tg(Prnp-MAPT*P301L)JNPL3Hlmc), males exhibit a significant reduction of Tau phosphorylation in the hippocampus and medulla oblongata, as well as a reduction in the limb-clasping response.
Lopera F, Marino C, Chandrahas AS, O'Hare M, Villalba-Moreno ND, Aguillon D, Baena A, Sanchez JS, Vila-Castelar C, Ramirez Gomez L, Chmielewska N, Oliveira GM, Littau JL, Hartmann K, Park K, Krasemann S, Glatzel M, Schoemaker D, Gonzalez-Buendia L, Delgado-Tirado S, Arevalo-Alquichire S, Saez-Torres KL, Amarnani D, Kim LA, Mazzarino RC, Gordon H, Bocanegra Y, Villegas A, Gai X, Bootwalla M, Ji J, Shen L, Kosik KS, Su Y, Chen Y, Schultz A, Sperling RA, Johnson K, Reiman EM, Sepulveda-Falla D, Arboleda-Velasquez JF, Quiroz YT. Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man. Nat Med. 2023 May;29(5):1243-1252. doi: 10.1038/s41591-023-02318-3. Epub 2023 May 15. (Medline PMID: 37188781)
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