Abstract
A reduced concentration of Aβ1−42 in CSF is one of the established biomarkers of Alzheimer's disease. Reduced CSF concentrations of Aβ1−42 have also been shown in multiple sclerosis, viral encephalitis and bacterial meningitis. As neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease, an infectious origin of the disease has been proposed. According to this hypothesis, amyloid pathology is a consequence of a microbial infection and the resulting immune defense. Accordingly, changes in CSF levels of amyloid-β peptides should be similar in AD and inflammatory brain diseases. Aβ1−42 and Aβ1−40 levels were measured in cerebrospinal fluid by ELISA and Western blotting in 34 patients with bacterial meningitis (n = 9), multiple sclerosis (n = 5) or Alzheimer's disease (n = 9) and in suitable controls (n = 11). Reduced concentrations of Aβ1−42 were detected in patients with bacterial meningitis, multiple sclerosis and Alzheimer's disease. However, due to a concurrent reduction in Aβ1−40 in multiple sclerosis and meningitis patients, the ratio of Aβ1−42/Aβ1−40 was reduced only in the CSF of Alzheimer's disease patients. Urea-SDS-PAGE followed by Western blotting revealed that all Aβ peptide variants are reduced in bacterial meningitis, whereas in Alzheimer's disease, only Aβ1−42 is reduced. These results have two implications. First, they confirm the discriminatory diagnostic power of the Aβ1−42/Aβ1−40 ratio. Second, the differential pattern of Aβ peptide reductions suggests that the amyloid pathology in meningitis and multiple sclerosis differs from that in AD and does not support the notion of AD as an infection-triggered immunopathology.
Highlights
In addition to amyloid plaque deposition, neuroinflammation is one of the neuropathological hallmarks of Alzheimer’s disease (AD) (Heneka et al, 2015)
Amyloid pathology was evaluated by the Aβ42/Aβ40 ratio, tau pathology was evaluated by phosphotau levels, and neurodegeneration was evaluated by total-tau levels and temporo-parietal atrophy in the MRI scan
The concentration of Aβ peptide 1-42 (Aβ1−42) in cerebrospinal fluid (CSF) is reduced in patients with AD, multiple sclerosis (MS) and bacterial meningitis
Summary
In addition to amyloid plaque deposition, neuroinflammation is one of the neuropathological hallmarks of Alzheimer’s disease (AD) (Heneka et al, 2015). The secretion of Aβ peptides during inflammation and the observation of anti-infective properties of Aβ peptides support the idea that the production of Aβ peptides provides an immune defense (Spitzer et al, 2010, 2016; Condic et al, 2014; Kumar et al, 2016) These and other findings have culminated in the formulation of the infection hypothesis of AD (Miklossy, 2011). The concentration of Aβ1−42 in relation to Aβ1−40, the most abundant Aβ peptide variant, was found to be superior to Aβ1−42 alone as a biomarker for AD (Lewczuk et al, 2004, 2015a,b; Janelidze et al, 2016; Niemantsverdriet et al, 2017) If this imbalance between Aβ42 and Aβ40 that is observed in AD could be found in inflammatory brain diseases, those data would further support the infection hypothesis of AD
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