Flotillin: A Promising Biomarker for Alzheimer's Disease.

Mohd. Farooq Shaikh,Christina Piperi,Efthalia Angelopoulou,Yam Nath Paudel

doi:10.3390/jpm10020020

Abstract

Alzheimer’s disease (AD) is characterized by the accumulation of beta amyloid (Aβ) in extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) mainly consisting of tau protein. Although the exact etiology of the disease remains elusive, accumulating evidence highlights the key role of lipid rafts, as well as the endocytic pathways in amyloidogenic amyloid precursor protein (APP) processing and AD pathogenesis. The combination of reduced Aβ42 levels and increased phosphorylated tau protein levels in the cerebrospinal fluid (CSF) is the most well established biomarker, along with Pittsburgh compound B and positron emission tomography (PiB-PET) for amyloid imaging. However, their invasive nature, the cost, and their availability often limit their use. In this context, an easily detectable marker for AD diagnosis even at preclinical stages is highly needed. Flotillins, being hydrophobic proteins located in lipid rafts of intra- and extracellular vesicles, are mainly involved in signal transduction and membrane–protein interactions. Accumulating evidence highlights the emerging implication of flotillins in AD pathogenesis, by affecting APP endocytosis and processing, Ca2+ homeostasis, mitochondrial dysfunction, neuronal apoptosis, Aβ-induced neurotoxicity, and prion-like spreading of Aβ. Importantly, there is also clinical evidence supporting their potential use as biomarker candidates for AD, due to reduced serum and CSF levels that correlate with amyloid burden in AD patients compared with controls. This review focuses on the emerging preclinical and clinical evidence on the role of flotillins in AD pathogenesis, further addressing their potential usage as disease biomarkers.

Highlights

Alzheimer’s disease (AD) is pathologically characterized by the accumulation of beta amyloid (Aβ), a peptide of 40 or 42 amino acids, in extracellular senile plaques, as well as intracellular neurofibrillary tangles (NFTs) mainly consisting of tau protein [1,2]
These findings suggest that flotillin-positive exosomes may play a key role in AD pathogenesis and be implicated in the prion-like propagation of Amyloid β (Aβ) pathology in AD
There is evidence indicating that clathrin-independent endocytic pathways may not play a significant role in amyloid-β precursor protein (APP) processing, since flotillin levels have been shown to remain unchanged in mutant APP transgenic mice, compared with proteins associated with clathrin-dependent pathways [53]

Summary

Introduction

Alzheimer’s disease (AD) is pathologically characterized by the accumulation of beta amyloid (Aβ), a peptide of 40 or 42 amino acids, in extracellular senile plaques, as well as intracellular neurofibrillary tangles (NFTs) mainly consisting of tau protein [1,2]. The combined estimation of reduced Aβ42 levels and increased phosphorylated tau protein levels in the cerebrospinal fluid (CSF) is the most well established biomarker for the diagnosis of the disease, along with Pittsburgh compound B and positron emission tomography (PiB-PET) for amyloid imaging [7,8,9] Both methods can relatively reliably detect AD at prosymptomatic stages [8,9], the lumbar puncture required for CSF collection is an invasive procedure demanding specialized staff technical skills and cannot be carried out in primary care settings [10]. We summarize the emerging preclinical and clinical evidence on the role of flotillins in AD pathogenesis, and discuss their potential usage as biomarker candidates (Figure 1) for AD along with possible limitations

The Role of Endocytic Pathway and Exosome Release in AD Pathogenesis

Evidence from Human Studies

Main Findings

Evidence from In Vitro Studies

Flotillin as a Novel Biomarker Candidate for AD

Findings

Conclusions