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Activity-induced MEMRI cannot detect functional brain anomalies in the APPxPS1-Ki mouse model of Alzheimer's disease
Alexandre Androuin1, Yah-Se Abada1, Myriam Ly1,2
1Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France.
Abstract:
Alzheimer's disease (AD) is the most common cause of dementia. Aside neuropathological lesions, abnormal neuronal activity and brain metabolism are part of the core symptoms of the disease. Activity-induced Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) has been proposed as a powerful approach to visualize evoked brain activity in rodents. Here, we evaluated the relevance of MEMRI in measuring neuronal (dys-)function in the APPxPS1 knocked-in (KI) mouse model of AD. Brain anomalies were firstly demonstrated in APPxPS1-Ki mice using cognitive testing (memory impairment) and histological mapping of immediate early gene products (decreased density of fos-positive neurons). Paradoxically, MEMRI analyses were not able to confirm the occurrence of neuronal hypoactivities in vivo. We then performed a neuropathological analysis that highlighted an abnormal increased permeability of the blood-brain barrier (BBB) in APPxPS1-Ki mice. We hypothesized that diffuse weakening of the BBB results in an uncontrolled diffusion of the MR contrast agent and a lack of correlation between manganese accumulation and neuronal activity. These results bring to light a limitation of the activity-induced MEMRI approach when applied to the APPxPS1-Ki mouse model as well as other mouse models harboring a compromised BBB.
Insights
Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) struggles to measure brain activity in Alzheimer's disease (AD) mouse models due to blood-brain barrier (BBB) issues. This limitation affects MEMRI
Area of Science:
- Neuroscience
- Biomedical Imaging
- Alzheimer's Disease Research
Background:
- Alzheimer's disease (AD) is a leading cause of dementia, characterized by neuropathology and altered brain activity.
- Abnormal neuronal activity and metabolism are core symptoms of AD.
- Activity-induced Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) is a technique used to visualize brain activity in rodents.
Purpose of the Study:
- To evaluate the utility of MEMRI for assessing neuronal function in the APPxPS1 knocked-in (KI) mouse model of AD.
- To investigate the relationship between cognitive deficits, neuronal activity, and MEMRI findings in this AD model.
Main Methods:
- Cognitive testing was performed to assess memory impairment in APPxPS1-KI mice.
- Histological analysis mapped immediate early gene products (e.g., fos) to evaluate neuronal activity.
- In vivo MEMRI was employed to measure brain activity.
- Neuropathological analysis assessed blood-brain barrier (BBB) integrity.
Main Results:
- APPxPS1-KI mice exhibited memory deficits and reduced fos-positive neurons, indicating impaired neuronal function.
- MEMRI analyses did not detect the expected neuronal hypoactivity in vivo.
- Pathological examination revealed increased blood-brain barrier permeability in APPxPS1-KI mice.
- This BBB compromise likely led to uncontrolled contrast agent diffusion, confounding MEMRI results.
Conclusions:
- Activity-induced MEMRI may be limited in AD mouse models with compromised blood-brain barriers.
- Weakened BBB integrity can lead to inaccurate interpretations of neuronal activity using MEMRI.
- Further methodological considerations are needed when applying MEMRI to models with BBB disruption.