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14-3-3 -reported early synaptic injury in Alzheimer's disease is independently mediated by sTREM2
Marcel S Woo1, Johanna Nilsson2, Joseph Therriault3,4
1Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
Introduction:
Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears.
Methods:
We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta () as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages.
Results:
14-3-3 was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss.
Conclusions:
Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.
Insights
Microglia activation, indicated by sTREM2, drives early synaptic damage in Alzheimer's disease before significant tau buildup. This highlights microglia's role in disease progression, even preceding later stage damage from tau and astrogliosis.
Area of Science:
- Neuroscience
- Neuropathology
- Biomarker Research
Background:
- Synaptic loss is a hallmark of Alzheimer's disease (AD), occurring early and linked to tau aggregation and microglia activation.
- The precise role of microglia activation in initiating synaptic damage before tau pathology is not fully understood.
Purpose of the Study:
- To investigate the independent contribution of microglia activation to synaptic injury in early Alzheimer's disease.
- To explore the relationship between synaptic degradation biomarkers and other AD pathologies across the disease continuum.
Main Methods:
- Studied 104 participants across the AD spectrum.
- Measured 14-3-3 zeta/delta as a synaptic degradation biomarker in cerebrospinal fluid.
- Utilized fluid and imaging biomarkers for tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation.
- Employed correlation analyses and structural equation modeling.
Main Results:
- Elevated 14-3-3 zeta/delta was observed with amyloid pathology, preceding detectable hippocampal volume loss.
- Early synaptic damage correlated with amyloidosis and tau load, and independently with sTREM2 (a microglia marker).
- In later stages, tau and astrogliosis also contributed to synaptic loss.
Conclusions:
- Microglia activation, specifically via sTREM2, mediates synaptic injury early in Alzheimer's disease, even before significant tau accumulation.
- This underscores the critical role of microglia in the early propagation of Alzheimer's disease pathology.
