Plasma autoantibodies to glial fibrillary acidic protein (GFAP) react with brain areas according to Braak staging of Parkinson’s disease

Abstract

Idiopathic Parkinson’s disease (PD) is characterized by a progredient degeneration of the brain, starting at deep subcortical areas such as the dorsal motor nucleus of the glossopharyngeal and vagal nerves (DM) (stage 1), followed by the coeruleus–subcoeruleus complex; (stage 2), the substantia nigra (SN) (stage 3), the anteromedial temporal mesocortex (MC) (stage 4), high-order sensory association areas and prefrontal fields (HC) (stage 5) and finally first-order sensory association areas, premotor areas, as well as primary sensory and motor field (FC) (stage 6). Autoimmunity might play a role in PD pathogenesis. Here we analyzed whether anti-brain autoantibodies differentially recognize different human brain areas and identified autoantigens that correlate with the above-described dissemination of PD pathology in the brain. Brain tissue was obtained from deceased individuals with no history of neurological or psychiatric disease and no neuropathological abnormalities. Tissue homogenates from different brain regions (DM, SN, MC, HC, FC) were subjected to SDS-PAGE and Western blot. Blots were incubated with plasma samples from 30 PD patients and 30 control subjects and stained with anti-IgG antibodies to detect anti-brain autoantibodies. Signals were quantified. Prominent autoantigens were identified by 2D-gel-coupled mass spectrometry sequencing. Anti-brain autoantibodies are frequent and occur both in healthy controls and individuals with PD. Glial fibrillary acidic protein (GFAP) was identified as a prominent autoantigen recognized in all plasma samples. GFAP immunoreactivity was highest in DM areas and lowest in FC areas with no significant differences in anti-GFAP autoantibody titers between healthy controls and individuals with PD. The anti-GFAP autoimmunoreactivity of different brain areas correlates with the dissemination of histopathological neurodegeneration in PD. We hypothesize that GFAP autoantibodies are physiological but might be involved as a cofactor in PD pathogenesis secondary to a leakage of the blood–brain barrier.

Plasma glial fibrillary acidic protein as a biomarker of disease progression in Parkinson’s disease: a prospective cohort study

“…Growing evidence suggests a correlation between GFAP and PD pathology [ 1 , 32 – 34 ]. Reportedly, brain areas that are destroyed early in the development of PD have particularly high levels of GFAP [ 3 ]. An animal study found the injection of Adeno-GFAP-GFP virus into the substantia nigra pars compacta caused severe reactive astrogliosis and exacerbated the accumulation of α-synuclein [ 1 ].…”

“…Participants were recruited between February 2015 and November 2020 and followed for up to 5 years. The inclusion criteria included the following: [ 1 ] patients had a disease duration of less than 3 years at the time of enrollment; [ 2 ] the clinical picture as well as the brain magnetic resonance imaging (MRI) excluded vascular parkinsonism and atypical parkinsonism; [ 3 ] patients were willing to follow-up annually and were diagnosed with clinically established PD at the last follow-up according to the MDS clinical diagnostic criteria [ 16 ].…”

“…Research has highlighted the pivotal role of reactive astrogliosis in the pathogenesis of Parkinson’s disease (PD) [ 1 , 2 ]. Studies have demonstrated that brain areas that are destroyed early in the development of PD have particularly high levels of GFAP and that there is an enteric glial reaction that leads to the overexpression of GFAP in PD patients [ 3 , 4 ].…”

Serum Biomarkers of Olfactory Identification Deficits in Patients with Parkinson’s Disease

“…Second, astrocytes can (1) release a variety of neurotoxic chemokines and cytokines, such as IL-6 [18,41,52,53]; (2) recruit and activate microglia, causing inflammatory damage [54]; and (3) present antigens and activate T-cells [55], causing immune damage. Third, astrocytes can provide antigens for anti-GFAP autoimmunoreactivity from peripheral blood in the context of leakage of the blood-brain barrier because of α-syn deposition [56,57]. Therefore, α-syn deposition can result in astrogliosis, astrocytic dysfunction, and eventually dysosmia.…”