Flotillin is a Novel Diagnostic Blood Marker of Alzheimer’s Disease

Abstract

Currently, best-characterized indicators for Alzheimer's disease (AD) diagnosis are the decreased levels of amyloid-␤ protein 42 and increased levels of phosphorylated tau in cerebrospinal fluid (CSF). The positron emission tomography (PET) imaging with Pittsburgh compound B (PiB) is also used in AD diagnosis by visualizing amyloid deposition in the brain. These methods are invasive or expensive; therefore, less invasive and easily detectable blood biomarkers are required. Because our previous study showed that flotillin release, a marker of exosomes, was attenuated by A␤, we designed the present study to determine whether flotillin level could be reduced in CSF and/or serum of patients with AD. In this study, we analyzed flotillin levels in CSF and serum of non-AD controls, patients with AD and mild cognitive impairment (MCI) by western blotting. Flotillin levels in cerebroventricular fluid (CVF) and serum of AD, vascular dementia (VaD), and non-AD autopsy cases were also analyzed. Flotillin levels significantly decreased in the CSF and serum of AD patients compared with those of non-AD controls, respectively. Moreover, in patients with MCI due to AD determined by PiB-PET, CSF and serum flotillin levels significantly decreased compared with those of patients with MCI due to non-AD. Flotillin levels remained unchanged in CVF and serum of autopsy cases diagnosed as VaD. Serum flotillin level is negatively associated with brain amyloid deposition indicated as PiB uptake. These results demonstrate that serum flotillin level can serve as one of the blood markers for estimation of brain amyloid deposition and early diagnosis of AD.

Flotillin: A Promising Biomarker for Alzheimer’s Disease

“…Proteomic analyses have already indicated that flotillins are constituents of CSF-derived exosomes [58,59]. Importantly, flotillin levels can be relatively easily measured by ELISA method and/or immunoblot analysis [10], providing a significant advantage compared with other biomarker candidates that may require more expensive and specialized equipment.…”

“…Interestingly, a recent clinical study has indicated that flotillin levels were lower not only in the CSF, but also in the serum of AD patients, compared with subjects with mild cognitive impairment (MCI) or age-matched non-AD controls [10]. Additionally, CSF and serum flotillin levels have been shown to be reduced in patients with AD-related MCI, compared with non-AD-related MCI (determined by PiB-PET) [10].…”

“…Interestingly, a recent clinical study has indicated that flotillin levels were lower not only in the CSF, but also in the serum of AD patients, compared with subjects with mild cognitive impairment (MCI) or age-matched non-AD controls [10]. Additionally, CSF and serum flotillin levels have been shown to be reduced in patients with AD-related MCI, compared with non-AD-related MCI (determined by PiB-PET) [10]. Investigation of postmortem brain tissues further revealed that flotillin levels were also lower in the cerebroventricular fluid (CVF) samples obtained from AD patients compared with subjects with vascular dementia [10].…”

“…Additionally, CSF and serum flotillin levels have been shown to be reduced in patients with AD-related MCI, compared with non-AD-related MCI (determined by PiB-PET) [10]. Investigation of postmortem brain tissues further revealed that flotillin levels were also lower in the cerebroventricular fluid (CVF) samples obtained from AD patients compared with subjects with vascular dementia [10]. Furthermore, flotillin levels have been found to be negatively correlated with amyloid burden, as shown by the mean cortical PiB retention levels in PiB-PET [10].…”

“…The combined estimation of reduced Aβ 42 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]. Although 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]. On the other hand, PiB-PET is quite expensive and not available worldwide.…”