Intracellular fibril formation, calcification, and enrichment of chaperones, cytoskeletal, and intermediate filament proteins in the adult hippocampus CA1 following neonatal exposure to the nonprotein amino acid BMAA
Artikel i vetenskaplig tidskrift, 2015

The environmental neurotoxin beta-N-methylamino-l-alanine (BMAA) has been implicated in the etiology of neurodegenerative disease, and recent studies indicate that BMAA can be misincorporated into proteins. BMAA is a developmental neurotoxicant that can induce long-term learning and memory deficits, as well as regionally restricted neuronal degeneration and mineralization in the hippocampal CA1. The aim of the study was to characterize long-term changes (2 weeks to 6 months) further in the brain of adult rats treated neonatally (postnatal days 9-10) with BMAA (460 mg/kg) using immunohistochemistry (IHC), transmission electron microscopy, and laser capture microdissection followed by LC-MS/MS for proteomic analysis. The histological examination demonstrated progressive neurodegenerative changes, astrogliosis, microglial activation, and calcification in the hippocampal CA1 3-6 months after exposure. The IHC showed an increased staining for alpha-synuclein and ubiquitin in the area. The ultrastructural examination revealed intracellular deposition of abundant bundles of closely packed parallel fibrils in neurons, axons, and astrocytes of the CA1. Proteomic analysis of the affected site demonstrated an enrichment of chaperones (e.g., clusterin, GRP-78), cytoskeletal and intermediate filament proteins, and proteins involved in the antioxidant defense system. Several of the most enriched proteins (plectin, glial fibrillar acidic protein, vimentin, Hsp 27, and ubiquitin) are known to form complex astrocytic inclusions, so-called Rosenthal fibers, in the neurodegenerative disorder Alexander disease. In addition, TDP-43 and the negative regulator of autophagy, GLIPR-2, were exclusively detected. The present study demonstrates that neonatal exposure to BMAA may offer a novel model for the study of hippocampal fibril formation in vivo.

Proteomics

Ubiquitin

ALS/PDC

Alexander disease

TDP-43

alpha-Synuclein

Författare

Oskar Karlsson

Uppsala universitet

A. L. Berg

Medical Products Agency

AstraZeneca AB

Jörg Hanrieder

Chalmers, Kemi och kemiteknik, Kemi och biokemi, Analytisk kemi

G. Arnerup

AstraZeneca AB

A. K. Lindstrom

AstraZeneca AB

Eva B. Brittebo

Uppsala universitet

Archives of Toxicology

0340-5761 (ISSN) 1432-0738 (eISSN)

Vol. 89 423-436

Ämneskategorier

Farmakologi och toxikologi

DOI

10.1007/s00204-014-1262-2