Pathological (Dis)Similarities in Neuronal Exosome-Derived Synaptic and Organellar Marker Levels Between Alzheimer’s Disease and Frontotemporal Dementia

Abstract

Background: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are pathologically distinct neurodegenerative disorders with certain overlap in cognitive and behavioral symptoms. Both AD and FTD are characterized by synaptic loss and accumulation of misfolded proteins, albeit, in different regions of the brain. Objective: To investigate the synaptic and organellar markers in AD and FTD through assessment of the levels of synaptic protein, neurogranin (Ng) and organellar proteins, mitofusin-2 (MFN-2), lysosomal associated membrane protein-2 (LAMP-2), and golgin A4 from neuronal exosomes. Methods: Exosomes isolated from the plasma of healthy controls (HC), AD and FTD subjects were characterized using transmission electron microscopy. Neurodegenerative status was assessed by measurement of neurofilament light chain (NfL) using Simoa. The pooled exosomal extracts from each group were analyzed for Ng, MFN-2, LAMP-2, and golgin A4 by western blot analysis using enhanced chemiluminescence method of detection. Results: The densitometric analysis of immunoreactive bands demonstrated a 65% reduction of Ng in AD and 53% in FTD. Mitochondrial protein MFN-2 showed a significant reduction by 32% in AD and 46% in FTD. Lysosomal LAMP-2 and Golgi complex associated golgin A4 were considerably increased in both AD and FTD. Conclusion: Changes in Ng may reflect the ongoing synaptic degeneration that are linked to cognitive disturbances in AD and FTD. Importantly, the rate of synaptic degeneration was more pronounced in AD. Changes to a similar extent in both the dementia groups in organellar proteins indicates shared mechanisms of protein accumulation/degradation common to both AD and FTD.

Unveiling the Complex Role of Exosomes in Alzheimer’s Disease

“…Exosomal contents can be used as biomarkers to differentiate AD from normal controls, MCI as well as other forms of dementia such as fronto-temporal dementia. In a study by Krishna et al, 160 the synaptic and organellar markers in AD and frontotemporal dementia (FTD) are investigated by assessing the levels of synaptic protein, neurogranin (Ng), and organellar proteins, mitofusin-2 (MFN-2), lysosomal associated membrane protein-2 (LAMP2), and golgin A4 from neuronal exosomes. Exosomes obtained from the plasma of healthy controls (HC), AD and FTD subjects were analyzed.…”

“…Crucially, alterations in the levels of synaptic protein, neurogranin (Ng) and MFN-2, LAMP2, and golgin A4 from neuronal exosomes are helpful to distinguish AD from normal controls and FTD. 160 The two-stage-sectional investigation by Jia et al 161 examined the potential of exosomal synaptic proteins as a predictor of asymptomatic Alzheimer’s disease. The first trial included participants with preclinical AD and controls, while the second study confirmed the findings in familial AD.…”

Introduction to The Special Issue: Novel Molecular Pathways and Therapeutic Challenges in Neurodegenerative Diseases

“…Guo and team [32] highlight the novel roles of meningeal lymphatic vessels in AD, while Zhang et al [33] highlight the significant role of necroptosis in AD and its relevance for novel biomarker discovery and future drug targets. Krishna and colleagues [34] provide new dimensions on pathological dissimilarities in neuronal exosome-derived synaptic networking between AD and frontotemporal dementia. Additionally, Naren et al [35] give insights into the key role of mitochondria health in brain disorders and provide new ideas on mitochondrial integrity and healthy functional mitochondria as key in brain health.…”