Editing Iowa Mutation Modeling Program (section)

==== 2.2 Empirical anchors from Tomidokoro et al. (2010) ====
The working hypothesis is grounded in the following observations/arguments:

* A substantial fraction of deposited Aβ in Iowa brain tissue is post-translationally modified at residue 23: approximately 10–30% contains isoAsp23. <ref name="Tomidokoro2010_isoAsp">Tomidokoro Y. ''et al.'' (2010). Iowa Variant of Familial Alzheimer’s Disease: Accumulation of Posttranslationally Modified AβD23N in Parenchymal and Cerebrovascular Amyloid Deposits. (See discussion text reporting ∼10–30% isoAsp23.)</ref>
* D23N may act as a “fast track” to isoAsp formation because Asn deamidation typically produces isoAsp much faster than Asp isomerization (order-of-magnitude statement in the discussion). <ref name="Tomidokoro2010_fasttrack">Tomidokoro Y. ''et al.'' (2010). Discussion: Asn deamidation typically yields ∼30× faster isoAsp formation than Asp isomerization.</ref>
* isoAsp-bearing molecules exhibit enhanced ''in vitro'' fibrillization kinetics relative to wild-type, and D23N strongly accelerates fibrillization (shortened lag phase; much faster ThT kinetics). <ref name="Tomidokoro2010_ThT">Tomidokoro Y. ''et al.'' (2010). Discussion + Thioflavin-T kinetics section/figure: D23N drives dramatic acceleration; isoAsp contributes modestly but measurably.</ref>
* isoAsp at other Aβ sites (e.g., positions 1 and 7) is associated with decreased proteolytic sensitivity, suggesting isoAsp23 may also contribute to impaired clearance once aggregated. <ref name="Tomidokoro2010_clearance">Tomidokoro Y. ''et al.'' (2010). Discussion: isoAsp at positions 1 and 7 decreases proteolytic sensitivity; potential relevance to Iowa aggressiveness.</ref>