Plasma Levels of Neuron- and Astrocyte-Derived Exosomal Amyloid Beta1-42, Amyloid Beta1-40, and Phosphorylated Tau Levels in Schizophrenia Patients and Non-psychiatric Comparison Subjects: Relationships With Cognitive Functioning and Psychopathology.

Robert A Rissman,Dilip V Jeste,Ellen E Lee,James W Barlow,Charisse Winston-Gray

doi:10.3389/fpsyt.2020.532624

Robert A Rissman, Dilip V Jeste + Show 3 more

Open Access

https://doi.org/10.3389/fpsyt.2020.532624

Copy DOI

Abstract

Introduction: Cognitive deficits in people with schizophrenia (PWS) are a major predictor of disability and functioning, yet the underlying pathophysiology remains unclear. A possible role of amyloid and tau biomarkers (hallmarks of Alzheimer's disease) is still speculative in schizophrenia. Exosomes or extracellular vesicles, involved with cell-to-cell communication and waste removal, can be used to assay brain-based proteins from peripheral blood. To our knowledge, this is the first study of exosomal amyloid and tau protein levels in PWS.Methods: This cross-sectional study included 60 PWS and 60 age- and sex-comparable non-psychiatric comparison subjects (NCs), age range 26–65 years. Assessments of global cognitive screening, executive functioning, psychopathology, and physical measures were conducted. Exosomes were extracted and precipitated from fasting plasma and identified as neuron-derived exosomes (NDEs) or astrocyte-derived exosomes (ADEs). Human-specific ELISAs were used to assay levels of amyloid-beta 1-42 (Aβ42), amyloid-beta 1-40 (Aβ40), and phosphorylated T181 tau (P-T181-tau). Plasma assays for aging biomarkers (C-reactive protein and F2-isoprostanes) were also performed.Results: ADE-Aβ42 levels were higher in PWS compared to NCs, though the other exosomal markers were similar between the two groups. Higher ADE-P-T181-tau levels were associated with worse executive functioning. Among PWS, higher ADE-P-T181-tau levels were associated with less severe negative symptoms and increased F2-isoprostane levels. Astrocyte-derived Aβ marker levels were sensitive and specific in differentiating between diagnostic groups. Among PWS, Aβ40 levels differed most by exosomal origin.Discussion: Exosomal markers may provide novel insights into brain-based processes (e.g., aging, oxidative stress) from peripheral blood samples.

Highlights

Cognitive deficits in people with schizophrenia (PWS) are a major predictor of disability and functioning, yet the underlying pathophysiology remains unclear
Plasma exosomes derived from PWS and nonpsychiatric comparison subjects (NCs) were extracted, precipitated, and enriched against neuronal (L1-CAM) and astrocyte (GLAST/ACSA-1) sources by fluorescent activated cell sorting (FACS) (Figure 1A)
Plasma Neuronal-Derived Exosomes (NDEs) and ADEs were probed with exosome marker, Flotilin-1 (Figure 1B), neuronal lineage marker, NeuN, and astrocyte marker, Glial fibrillary acidic protein (GFAP)

Summary

Introduction

Cognitive deficits in people with schizophrenia (PWS) are a major predictor of disability and functioning, yet the underlying pathophysiology remains unclear. Exosomes or extracellular vesicles, involved with cell-to-cell communication and waste removal, can be used to assay brain-based proteins from peripheral blood. To our knowledge, this is the first study of exosomal amyloid and tau protein levels in PWS. Cognitive deficits in people with schizophrenia (PWS) are a major predictor of disability and functioning, yet there is limited understanding of the underlying pathophysiology of these impairments. In Alzheimer’s disease (AD), it has been hypothesized that pathological amyloid-beta (Aβ) and tau (hallmarks of AD) seed and spread from cell to cell in the brain [1, 2]. Though significant cognitive deficits are common in PWS, the roles of Aβ and tau biomarkers have not been clearly identified in schizophrenia

Methods

Results

Conclusion