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January 17, 2018

Dementia Shown Associated with Synaptic Dysfunction Rather Than Synaptic Loss

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  • Researchers from Canada and France have published results that challenge the view that Alzheimer's disease is accompanied by a significant, progressive loss of neurons and synapses. 

    Conducted among more than 170 subjects at various stages of Alzheimer's disease, the study (“Moderate Decline in Select Synaptic Markers in the Prefrontal Cortex (BA9) of Patients with Alzheimer’s Disease at Various Cognitive Stages”), which appears in Scientific Reports, shows that the disease is accompanied by a minor decline in neuronal and synaptic markers.

    “Synaptic loss, plaques and neurofibrillary tangles are viewed as hallmarks of Alzheimer’s disease (AD). This study investigated synaptic markers in neocortical Brodmann area 9 (BA9) samples from 171 subjects with and without AD at different levels of cognitive impairment. The expression levels of vesicular glutamate transporters (VGLUT1&2), glutamate uptake site (EAAT2), post-synaptic density protein of 95 kD (PSD95), vesicular GABA/glycine transporter (VIAAT), somatostatin (som), synaptophysin and choline acetyl transferase (ChAT) were evaluated. VGLUT2 and EAAT2 were unaffected by dementia. The VGLUT1, PSD95, VIAAT, som, ChAT and synaptophysin expression levels significantly decreased as dementia progressed,”write the investigators.

    “The maximal decrease varied between 12% (synaptophysin) and 42% (som). VGLUT1 was more strongly correlated with dementia than all of the other markers (polyserial correlation = –0.41). Principal component analysis using these markers was unable to differentiate the CDR [clinical dementia rating scale] groups from one another. Therefore, the status of the major synaptic markers in BA9 does not seem to be linked to the cognitive status of AD patients. The findings of this study suggest that the loss of synaptic markers in BA9 is a late event that is only weakly related to AD dementia.”

    "Much to our surprise, in studying the fate of eight neuronal and synaptic markers in our subjects' prefrontal cortices, we only observed very minor neuronal and synaptic losses. Our study therefore suggests that, contrary to what was believed, neuronal and synaptic loss is relatively limited in Alzheimer's disease. This is a radical change in thinking," explains Salah El Mestikawy, Ph.D., from the Douglas Mental Health University Institute, Canada and an associate professor at McGill University.

    The scientists also attempted to correlate all these minor synaptic losses with the subjects' level of dementia. Their results show that the declines in synaptic biomarkers had little impact on the participants' cognitive skills.

    The study implicitly suggests that dementia is associated with a synaptic dysfunction rather than the disappearance of synapses from the patient's cortex. Identifying this dysfunction could lead to the development of effective treatments for this disease.

    "Until now, therapeutic interventions have been aimed at slowing synaptic destruction. Based on our study, we are going to have to change our therapeutic approach," says Dr. El Mestikawy.

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