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Correlative Light and Electron Microscopy to Study Microglial Interactions with β-Amyloid Plaques
Published on: June 1, 2016
Microglial extracellular vesicles induce Alzheimer's disease-related cortico-hippocampal network dysfunction
Chiara Falcicchia1, Francesca Tozzi1,2, Martina Gabrielli3
1National Research Council (CNR) Institute of Neuroscience, Pisa 56124, Italy.
Abstract:
β-Amyloid is one of the main pathological hallmarks of Alzheimer's disease and plays a major role in synaptic dysfunction. It has been demonstrated that β-amyloid can elicit aberrant excitatory activity in cortical-hippocampal networks, which is associated with behavioural abnormalities. However, the mechanism of the spreading of β-amyloid action within a specific circuitry has not been elucidated yet. We have previously demonstrated that the motion of microglia-derived large extracellular vesicles carrying β-amyloid, at the neuronal surface, is crucial for the initiation and propagation of synaptic dysfunction along the entorhinal-hippocampal circuit. Here, using chronic EEG recordings, we show that a single injection of extracellular vesicles carrying β-amyloid into the mouse entorhinal cortex could trigger alterations in the cortical and hippocampal activity that are reminiscent of those found in Alzheimer's disease mouse models and human patients. The development of EEG abnormalities was associated with progressive memory impairment as assessed by an associative (object-place context recognition) and non-associative (object recognition) task. Importantly, when the motility of extracellular vesicles, carrying β-amyloid, was inhibited, the effect on network stability and memory function was significantly reduced. Our model proposes a new biological mechanism based on the extracellular vesicles-mediated progression of β-amyloid pathology and offers the opportunity to test pharmacological treatments targeting the early stages of Alzheimer's disease.
Insights
Extracellular vesicles carrying beta-amyloid (Aβ) spread Alzheimer's disease pathology, causing network dysfunction and memory loss. Inhibiting vesicle movement significantly reduced these effects, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Pathology
- Biochemistry
Background:
- Beta-amyloid (Aβ) is a key hallmark of Alzheimer's disease (AD), contributing to synaptic dysfunction and behavioral abnormalities.
- The precise mechanism by which Aβ spreads within neural circuits remains unclear.
- Microglia-derived extracellular vesicles (EVs) carrying Aβ have been implicated in initiating and propagating synaptic dysfunction in the entorhinal-hippocampal circuit.
Purpose of the Study:
- To investigate the role of extracellular vesicle (EV)-mediated Aβ propagation in Alzheimer's disease (AD) pathogenesis.
- To determine if Aβ-carrying EVs injected into the entorhinal cortex can induce AD-like network and memory alterations.
- To assess the therapeutic potential of inhibiting EV motility in an AD model.
Main Methods:
- Chronic electroencephalography (EEG) recordings in mice.
- Stereotactic injection of Aβ-carrying EVs into the mouse entorhinal cortex.
- Assessment of memory function using object recognition and object-place context recognition tasks.
- Pharmacological inhibition of EV motility.
Main Results:
- Single injection of Aβ-carrying EVs induced EEG abnormalities in cortical and hippocampal networks, mimicking AD.
- EEG alterations correlated with progressive memory impairment in associative and non-associative tasks.
- Inhibiting EV motility significantly attenuated network instability and memory deficits.
- EV motility is crucial for the progression of Aβ pathology and associated cognitive decline.
Conclusions:
- Extracellular vesicles (EVs) mediate the spread of beta-amyloid (Aβ) pathology, driving network dysfunction and memory impairment in a mouse model.
- This study elucidates a novel mechanism for Aβ progression via EV motility.
- Targeting EV-mediated Aβ spread presents a promising therapeutic strategy for early-stage Alzheimer's disease.
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