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Updated: Jun 27, 2025
Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus
Published on: June 17, 2015
Selective targeting and modulation of plaque associated microglia via systemic hydroxyl dendrimer administration in
Caden M Henningfield1, Neelakshi Soni1, Ryan W Lee1
1Department of Neurobiology and Behavior, University of California, 3208 Biological Sciences III, Irvine, CA, 92697, USA.
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.
Insights
Hydroxyl dendrimers (HDs) target plaque-associated microglia (PAMs) in Alzheimer's disease models. This nanomedicine reduces amyloid-beta plaques and neuroinflammation, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Nanomedicine
- Immunology
Background:
- Microglia play a key role in Alzheimer's disease (AD) pathogenesis through sustained inflammatory responses around amyloid plaques.
- Targeting plaque-associated microglia (PAMs) specifically is crucial for therapeutic interventions without disrupting essential microglial functions.
Purpose of the Study:
- To investigate the potential of systemically administered hydroxyl dendrimers (HDs) to target PAMs in an AD mouse model.
- To demonstrate the biological effects of HDs conjugated to a CSF1R inhibitor on PAMs and AD pathology.
Main Methods:
- Hydroxyl dendrimers (HDs) were administered systemically to the 5xFAD mouse model of amyloidosis.
- HDs were conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113) and administered bi-weekly for 4 weeks.
- The effects on amyloid-beta (Aβ) levels, microglial numbers and plaque association, and gene expression were analyzed.
Main Results:
- Systemic administration of HDs successfully crossed the blood-brain barrier and were preferentially taken up by PAMs.
- Treatment led to significant reductions in Aβ plaques and microglial-plaque association in key brain regions.
- A notable downregulation of microglial, inflammatory, and synaptic gene expression was observed compared to controls.
Conclusions:
- Systemic administration of hydroxyl dendrimers (HDs) can effectively target and modulate plaque-associated microglia (PAMs).
- This nanomedicine approach shows promise for reducing AD pathology and neuroinflammation.
- HDs represent a potential therapeutic avenue for Alzheimer's disease by specifically targeting PAMs.
