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Aβ antibodies target not only amyloid plaques but also distinct brain cells and vessels

Wen, Gehua LU orcid ; Lindblom, Nils LU ; Zhan, Xiaoni LU ; Garcia-Ryde, Megg LU orcid ; Deierborg, Tomas LU orcid ; Kobro‐Flatmoen, Asgeir and Gouras, Gunnar K. LU orcid (2026) In Alzheimer's & Dementia 22(1). p.1-17
Abstract
BACKGROUND
Amyloid beta (Aβ) antibodies are the only therapies to slow cognitive decline in Alzheimer's disease (AD). Yet the sites where antibodies engage Aβ in the brain and mechanisms that lower Aβ are not fully understood. Defining Aβ antibody localizations in the brain is essential to understand how immunotherapy is beneficial for AD.

METHODS
N-terminal Aβ antibody 6E10 was injected via three different routes into different AD mouse models. N-terminal Aβ antibodies were empirically shown as most effective in AD mice. Antibody localization was examined in the brain after injections. Glymphatic dynamics were also evaluated.

RESULTS
As expected, Aβ antibody 6E10 bound to plaques but remarkably also localized... (More)
BACKGROUND
Amyloid beta (Aβ) antibodies are the only therapies to slow cognitive decline in Alzheimer's disease (AD). Yet the sites where antibodies engage Aβ in the brain and mechanisms that lower Aβ are not fully understood. Defining Aβ antibody localizations in the brain is essential to understand how immunotherapy is beneficial for AD.

METHODS
N-terminal Aβ antibody 6E10 was injected via three different routes into different AD mouse models. N-terminal Aβ antibodies were empirically shown as most effective in AD mice. Antibody localization was examined in the brain after injections. Glymphatic dynamics were also evaluated.

RESULTS
As expected, Aβ antibody 6E10 bound to plaques but remarkably also localized to vulnerable neurons, such as hippocampal CA1 pyramidal cells, as well as microglia, astrocytes, oligodendrocytes, perivascular macrophages, and blood vessels. Antibodies did not alter glymphatic function.

DISCUSSION
We provide detailed localizations of antibodies in AD mouse brains, offering insights into targets of Aβ antibody-based immunotherapy.

Highlights

Amyloid beta (Aβ) antibody 6E10 shows broad distribution across plaques and multiple cellular/vascular compartments in different Alzheimer's disease (AD) mouse models.
Localization of antibody 6E10 in AD mice was detected in selective neurons, astrocytes, microglia, perivascular macrophages (PVMs), and oligodendrocytes/oligodendrocyte precursor cells, and at the external aspects of blood vessels.
Intracellular human-specific Aβ antibody 6E10 appears related to phagocytic activity, as PVMs and microglia in wild-type mice also contained 6E10, or to intracellular Aβ, as 6E10 in neurons, and oligodendrocytes were only detected in AD mice.
Aβ antibody injections by different routes failed to augment glymphatic circulation in AD mice. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Alzheimer's & Dementia
volume
22
issue
1
article number
e71121
pages
1 - 17
publisher
Wiley
external identifiers
  • pmid:41566565
ISSN
1552-5279
DOI
10.1002/alz.71121
language
English
LU publication?
yes
id
b37ebd1c-b7e5-4d5b-8b13-e6be2d18e4d7
date added to LUP
2026-01-22 21:28:45
date last changed
2026-01-23 07:20:04
@article{b37ebd1c-b7e5-4d5b-8b13-e6be2d18e4d7,
  abstract     = {{BACKGROUND<br/>Amyloid beta (Aβ) antibodies are the only therapies to slow cognitive decline in Alzheimer's disease (AD). Yet the sites where antibodies engage Aβ in the brain and mechanisms that lower Aβ are not fully understood. Defining Aβ antibody localizations in the brain is essential to understand how immunotherapy is beneficial for AD.<br/><br/>METHODS<br/>N-terminal Aβ antibody 6E10 was injected via three different routes into different AD mouse models. N-terminal Aβ antibodies were empirically shown as most effective in AD mice. Antibody localization was examined in the brain after injections. Glymphatic dynamics were also evaluated.<br/><br/>RESULTS<br/>As expected, Aβ antibody 6E10 bound to plaques but remarkably also localized to vulnerable neurons, such as hippocampal CA1 pyramidal cells, as well as microglia, astrocytes, oligodendrocytes, perivascular macrophages, and blood vessels. Antibodies did not alter glymphatic function.<br/><br/>DISCUSSION<br/>We provide detailed localizations of antibodies in AD mouse brains, offering insights into targets of Aβ antibody-based immunotherapy.<br/><br/>Highlights<br/><br/>Amyloid beta (Aβ) antibody 6E10 shows broad distribution across plaques and multiple cellular/vascular compartments in different Alzheimer's disease (AD) mouse models.<br/>Localization of antibody 6E10 in AD mice was detected in selective neurons, astrocytes, microglia, perivascular macrophages (PVMs), and oligodendrocytes/oligodendrocyte precursor cells, and at the external aspects of blood vessels.<br/>Intracellular human-specific Aβ antibody 6E10 appears related to phagocytic activity, as PVMs and microglia in wild-type mice also contained 6E10, or to intracellular Aβ, as 6E10 in neurons, and oligodendrocytes were only detected in AD mice.<br/>Aβ antibody injections by different routes failed to augment glymphatic circulation in AD mice.}},
  author       = {{Wen, Gehua and Lindblom, Nils and Zhan, Xiaoni and Garcia-Ryde, Megg and Deierborg, Tomas and Kobro‐Flatmoen, Asgeir and Gouras, Gunnar K.}},
  issn         = {{1552-5279}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{1--17}},
  publisher    = {{Wiley}},
  series       = {{Alzheimer's & Dementia}},
  title        = {{Aβ antibodies target not only amyloid plaques but also distinct brain cells and vessels}},
  url          = {{http://dx.doi.org/10.1002/alz.71121}},
  doi          = {{10.1002/alz.71121}},
  volume       = {{22}},
  year         = {{2026}},
}