Format

Send to

Choose Destination
See comment in PubMed Commons below
Brain. 2008 Jun;131(Pt 6):1416-32. doi: 10.1093/brain/awm305. Epub 2008 Jan 29.

Argyrophilic grain disease.

Author information

1
Institut Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, carrer Feixa LLarga sn, 08907 Hospitalet de Llobregat, Spain. 8082ifa@comb.cat

Abstract

Argyrophilic grain disease (AGD) is a common sporadic neurodegenerative disease of old age characterized by the presence of argyrophilic grains (AGs)--dendritic-derived appendages as revealed with the Golgi method--together with pre-tangle neurons in the limbic system, which accounts for about 5% of all demented cases. AGs and pre-tangle neurons contain hyperphosphorylated 4R tau. This is associated with a typical 64 kDa and 68 kDa pattern, but also accompanied by tau truncated forms of low molecular mass, probably resulting from thrombin-mediated proteolysis. Hyperphosphorylated tau also accumulates in oligodendroglial-coiled bodies and in limbic astrocytes. Ballooning neurons in the amygdala are non-specific accompanying abnormalities. A new proposal for AG distribution considers four stages. Clinical symptoms largely depend on the extension of AGs together with the very common associated tauopathies, mainly Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and synucleinopathies. Pathogenesis of AG and related lesions herein proposed includes oxidative stress that is followed by increased expression of oxidative response markers, and activation of stress kinases (stress activated protein kinase and p38). These kinases together with glycogen synthase kinase 3beta co-localize with hyperphosphorylated tau deposits in neurons and glial cells, thus indicating a link between oxidative stress and tau phosphorylation in AGD. Hyperphosphorylated tau, in turn, co-localizes with p62/sequestosome 1 and ubiquitin, thus pointing to activation of protein aggregation and protein degradation pathways, respectively. Finally, AGs and tangles co-localize with mutant ubiquitin (UBB(+1)) resulting from molecular misreading of mRNA, thus supporting proteasome function impairment and, therefore, impelling accumulation of hyperphosphorylated tau in AGs and tangles. The sequestration of active kinases in AGs and tangles is an additional local cause of tau hyperphosphorylation.

PMID:
18234698
DOI:
10.1093/brain/awm305
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Silverchair Information Systems
    Loading ...
    Support Center