Selective targeting and modulation of plaque associated microglia via systemic hydroxyl dendrimer administration in an Alzheimer's disease mouse model

Alzheimers Res Ther. 2024 May 6;16(1):101. doi: 10.1186/s13195-024-01470-3.

Abstract

Background: In Alzheimer's disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue.

Methods: Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113).

Results: Treatment resulted in significant reductions in amyloid-beta (Aβ) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice.

Conclusions: This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.

Keywords: Alzheimer’s disease; Amyloid; Dendrimers; Inflammation; Microglia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Dendrimers*
  • Disease Models, Animal*
  • Humans
  • Mice
  • Mice, Transgenic*
  • Microglia* / drug effects
  • Microglia* / metabolism
  • Plaque, Amyloid* / drug therapy
  • Plaque, Amyloid* / pathology
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors

Substances

  • Dendrimers
  • Amyloid beta-Peptides
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Csf1r protein, mouse