Flotillin: A Promising Biomarker for Alzheimer’s Disease

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.

Vesicular Transport of Encapsulated microRNA between Glial and Neuronal Cells

“… Highly schematized representation of ( A ) the release of exosomes (EXs) and ( B ) the release and uptake of extracellular microvesicles (EMVs) in neural cells of the human central nervous system (CNS); both types of vesicular transport systems have been observed to operate in the brain between astroglial cells and neurons; ( A ) exosomes—when mature intracellular endosomes (also known as multi-vesicular bodies) containing intraluminal vesicles (ILVs; black outlined green spheres) fuse with the plasma membrane and empty their plasma membrane-encapsulated cargo, ILVs are released and, from being extracellular, they become exosomes (EX); these 30–100 nm diameter spheres contain various mixtures of proteins, lipids, proteolipids, cytokines, chemokines, microRNAs (miRNA), messenger RNAs (mRNA) and end-stage neurotoxic metabolic products, including 42 amino acid amyloid-beta (Aβ42) peptides, tau proteins and/or the lipid raft associated flotillin (Angelopoulou et al 2020 [ 29 ]; Hornung et al, 2020 [ 30 ]); EXs appear to play a central role in the spread of Aβ42 pathology and amyloidogenesis (Mathews and Levy 2019 [ 15 ]; Arbo et al, 2020 [ 6 ]; Peng et al, 2020 [ 31 ]); ( B ) extracellular microvesicles (EMVs)—the exterior plasma membrane of activated microglia (AM) can release (R) 100–1000 nm diameter EMVs directly from the outward blebbing of the plasma membrane of microglias and astrocytes and carry intracellular contents from their cells of origin; this includes various complex mixtures of proteins, lipids, proteolipids, miRNAs, mRNAs, end-stage metabolic products and cytokines and chemokines; together these EMV contents may be pathogenic and cause the spread of pro-inflammatory signaling and inflammatory neurodegeneration (Prada et al, 2018 [ 21 ]; Serpente et al, 2020 [ 22 ]; Vanherle et al, 2020 [ 4 ]). Microvesicular trafficking and the extracellular microvesicle uptake (U) by neurons (N) via directed translocation mechanisms (dashed black lines with black arrowheads) may occur via the direct fusion of the EMV membrane with the neuronal cell plasma membrane or by endocytosis (Stahl et al, 2019 [ 5 ]; Arbo et al, 2020 [ 6 ]; Hornung et al, 2020 [ 30 ]; Peng et al, 2020 [ 32 ]; Song et al, 2020 [ 9 ]; Upadhya et al, 2020 [ 20 ]).…”

Molecular and Imaging Biomarkers in Alzheimer’s Disease: A Focus on Recent Insights

“…Recent evidence has pointed out a role of flotillin as a novel AD biomarker [ 79 , 80 ]. This is a membrane-associated protein located in lipid rafts of intra- and extracellular vesicles; therefore, it plays important roles in signal transduction and membrane–protein interactions.…”

“…This is a membrane-associated protein located in lipid rafts of intra- and extracellular vesicles; therefore, it plays important roles in signal transduction and membrane–protein interactions. Regarding AD pathogenesis, flotillin is involved in several pathological processes, such as APP processing and endocytosis, mitochondrial dysfunction, Aβ-induced neurotoxicity and neuronal apoptosis [ 80 ]. A clinical study reported that flotillin levels were decreased in both CSF and serum of AD patients compared with MCI individuals or age-matched non-AD controls.…”

Neuronal Signaling Involved in Neuronal Polarization and Growth: Lipid Rafts and Phosphorylation

“…However, the development of super-resolution microscopy permitted the observed lipid rafts in various cell types, leading to the wider acceptance of this concept (Owen et al, 2012 ). There are several styles of super-resolution microscopy that use distinct probes; each of these methods has successfully permitted the visualization of lipid rafts (Tobin et al, 2014 ; Chen et al, 2015 ; Hartley et al, 2015 ; Stahley et al, 2016 ; Gao et al, 2017 ; Schlegel et al, 2019 ; Angelopoulou et al, 2020 ). These new results have contributed to models suggesting possible roles for lipid rafts in multiple cellular pathways (Raghunathan and Kenworthy, 2018 ).…”