Transport of Bispecific Amyloid-Beta/Transferrin Receptor 1 Antibodies in Alzheimer's Disease Tg-SwDI Mice
Author
Shuymuh Ladwena, Yefon
Term
4. term
Education
Publication year
2026
Submitted on
2026-06-03
Pages
45
Abstract
This project examines how bispecific antibodies that bind both amyloid‑beta (Aβ) and transferrin receptor 1 (TfR1) are transported and distributed in the brain of TgSwDI Alzheimer’s disease model mice. The goal was to determine whether TfR1 targeting enhances brain uptake and how the route of administration shapes distribution. Transgenic TgSwDI and wild‑type mice received antibodies either systemically or by intracerebroventricular (ICV) injection. Brains were collected, cryosectioned, and analyzed by immunohistochemistry and fluorescence microscopy to map antibody distribution, Aβ localization, and capillary basement membrane protein expression (including beta‑dystroglycan). TgSwDI mice showed widespread Aβ deposition in neuronal cell bodies in the forebrain and along major vessels. Systemic administration resulted in minimal passage across the blood–brain barrier with signal largely confined to vascular structures, whereas ICV delivery produced broad distribution via the ventricular system, including the ependyma and choroid plexus. Anti‑Aβ antibodies formed localized periventricular accumulations that extended into surrounding tissue, unlike more diffuse IgG, consistent with target‑specific binding to amyloid deposits. The bispecific anti‑Aβ/TfR1 antibody did not improve brain uptake in this model, indicating limited effectiveness of TfR1‑mediated transport under the tested conditions. Beta‑dystroglycan staining was uniformly distributed across cerebral capillaries with no detectable group differences despite substantial amyloid burden, suggesting changes may be predominantly functional rather than structural. Overall, the findings highlight the central role of the blood–brain barrier in limiting antibody delivery, the potential of CSF‑mediated distribution, and the need for improved barrier‑crossing strategies to advance antibody‑based approaches for Alzheimer’s disease.
Dette projekt undersøger, hvordan bispecifikke antistoffer, der binder både amyloid‑beta (Aβ) og transferrinreceptor 1 (TfR1), transporteres og fordeles i hjernen hos Alzheimer-modellen TgSwDI mus. Formålet var at vurdere, om TfR1-målretning forbedrer antistoffers optag i hjernen, og hvordan administrationsvejen påvirker fordelingen. Transgene TgSwDI og vilttype mus fik antistoffer enten systemisk eller via intraventrikulær (ICV) injektion. Efterfølgende blev hjernen udtaget, kryosnittet og analyseret med immunhistokemi og fluorescensmikroskopi for at kortlægge antistofdistribution, Aβ-lokalisering og udtryk af kapillærbasalmembranproteiner (herunder beta-dystroglycan). I TgSwDI-mus sås udbredt Aβ-aflejring i nervecellelegemer i forhjernen og langs større blodkar. Systemisk administration gav minimal passage over blod-hjerne-barrieren med signal overvejende i karnære strukturer, mens ICV-tilførsel medførte bred fordeling via ventrikelsystemet, herunder ependym og plexus choroideus. Anti‑Aβ antistoffer dannede lokaliserede periventrikulære ophobninger, der strakte sig ind i omgivende væv, i modsætning til mere diffus IgG-fordeling, hvilket er foreneligt med målrettet binding til amyloide aflejringer. Den bispecifikke anti‑Aβ/TfR1‑antistofvariant forbedrede ikke hjernetilførslen i denne model, hvilket peger på begrænset effektivitet af TfR1‑medieret transport under de afprøvede betingelser. Beta‑dystroglycan var ensartet fordelt i kapillærer uden påviselige gruppeforskelle, trods udtalt amyloidbyrde, hvilket indikerer, at ændringerne kan være mere funktionelle end strukturelle. Samlet understreger resultaterne blod‑hjerne‑barrierens betydning for antistoflevering, potentialet ved CSF‑medieret distribution, og behovet for forbedrede strategier til målretning over barrierer i udviklingen af antistofbaserede tilgange mod Alzheimer’s sygdom.
[This apstract has been generated with the help of AI directly from the project full text]