ABSTRACT
Blood tests are in need, in the clinical diagnosis of Alzheimer's disease (AD) as minimally invasive and less expensive alternatives to cerebrospinal fluid and neuroimaging methods. On these lines, single molecule array (Simoa) analysis of amyloid-ß (Aß42), total tau (t-tau), phospho-tau (p-tau 181), and neurofilament L (NfL) in the plasma samples of AD subjects, healthy controls (HC), and non-AD subjects was conducted. Findings from this study suggest that a panel of multiple plasma biomarkers (NfL, Aß42, t-tau, and p-tau 181) combined with the clinical assessments could support differential diagnosis of AD and other dementias from healthy controls.
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.
Subject(s)
Alzheimer Disease , Exosomes , Frontotemporal Dementia , Humans , Alzheimer Disease/metabolism , Frontotemporal Dementia/diagnosis , Exosomes/metabolism , Golgi Matrix Proteins/metabolism , Neurons/metabolism , NeurograninABSTRACT
Based on the reduction of amyloid ß plaques, US FDA has recently approved Aducanumab as a disease modifying treatment for Alzheimer's disease (AD). With high pricing and the potential risks likely with this treatment, certainty of AD diagnosis becomes crucial. The current pilot study evaluated plasma levels of neurofilament L, an axonal injury marker and amyloid ß42, a major component of amyloid plaques for discriminating AD from non-AD dementia (NAD). Results with Simoa assays indicate that a combination of neurofilament L and amyloid ß42 can be considered as a screening tool in identifying eligible subjects for AD treatment/ clinical trials.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Alzheimer Disease/diagnosis , Biomarkers , Cross-Sectional Studies , Humans , Intermediate Filaments , Peptide Fragments , Pilot Projects , tau ProteinsABSTRACT
Prolidase enzyme, which catalyzes the final step in collagen metabolism can influence the cognitive functions through changes in extracellular matrix (ECM) resulting in altered synaptic connectivity in Alzheimer's disease (AD). In this study, it was found that the prolidase activity was significantly higher (p = 0.0016) in AD subjects (5.62 ± 2.05 U/ mL) than control group (4.45 ± 0.92 U/ mL). The increase was significant beginning at mild AD (p = 0.006) with an inverse correlation with HMSE scores (p = 0.0344), thus implying that prolidase mediated alterations in ECM may be associated with the cognitive deficits seen in AD.
