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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Established Beta Amyloid Pathology Is Unaffected by TREM2 Elevation in Reactive Microglia in an Alzheimer's Disease
Qiuju Yuan1,2, Xiaodong Liu3, Yi Zhang4
1Faculty of Medicine, School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong.
Abstract:
Several genetic studies have identified a rare variant of triggering receptor expressed on myeloid cells 2 (TREM2) as a risk factor for Alzheimer's disease (AD). However, findings on the effects of TREM2 on Aβ deposition are quite inconsistent in animal studies, requiring further investigation. In this study, we investigated whether elevation of TREM2 mitigates Aβ pathology in TgCRND8 mice. We found that peripheral nerve injury resulted in a robust elevation of TREM2 exclusively in reactive microglia in the ipsilateral spinal cord of aged TgCRND8 mice at the age of 20 months. TREM2 expression appeared on day 1 post-injury and the upregulation was maintained for at least 28 days. Compared to the contralateral side, neither amyloid beta plaque load nor soluble Aβ40 and Aβ42 levels were attenuated upon TREM2 induction. We further showed direct evidence that TREM2 elevation in reactive microglia did not affect amyloid-β pathology in plaque-bearing TgCRND8 mice by applying anti-TREM2 neutralizing antibody to selectively block TREM2. Our results question the ability of TREM2 to ameliorate established Aβ pathology, discouraging future development of disease-modifying pharmacological treatments targeting TREM2 in the late stage of AD.
Insights
Elevating triggering receptor expressed on myeloid cells 2 (TREM2) in Alzheimer's disease mouse models did not reduce amyloid-beta pathology. These findings suggest TREM2 may not be effective for treating established Alzheimer's disease.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Triggering receptor expressed on myeloid cells 2 (TREM2) variants are linked to Alzheimer's disease (AD) risk.
- Previous animal studies show inconsistent effects of TREM2 on amyloid-beta (Aβ) deposition.
Purpose of the Study:
- To investigate if elevated TREM2 can mitigate Aβ pathology in TgCRND8 mice.
Main Methods:
- Induced peripheral nerve injury in aged TgCRND8 mice to elevate TREM2 in reactive microglia.
- Measured Aβ plaque load and soluble Aβ40/Aβ42 levels.
- Utilized anti-TREM2 neutralizing antibodies to block TREM2 function.
Main Results:
- Peripheral nerve injury robustly elevated TREM2 in reactive microglia but did not attenuate Aβ plaque load or soluble Aβ levels.
- Blocking TREM2 with antibodies did not alter amyloid-beta pathology in plaque-bearing mice.
Conclusions:
- TREM2 elevation does not ameliorate established Aβ pathology in this Alzheimer's disease model.
- Targeting TREM2 for late-stage AD treatment may not be effective, questioning its disease-modifying potential.
