myelin-basic-protein and Supranuclear-Palsy--Progressive

Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood. An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic. Several proteins associated with neurodegenerative diseases, such as β-amyloid (Aβ) and α-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins. The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.

Topics: Animals; Brain; Cell Line, Tumor; Cellular Structures; Enzyme-Linked Immunosorbent Assay; Humans; Immunoprecipitation; Lewy Body Disease; Mice; Mice, Transgenic; Mutation; Myelin Basic Protein; Neuroblastoma; Phosphorylation; Supranuclear Palsy, Progressive; tau Proteins

C4d-immunoreactive complement-activated oligodendrocytes (C4d-CAOs) have been described in several neurodegenerative diseases but have not been studied in multiple sclerosis (MS). Here we report that such CAOs delineate miniature MS plaques of 300-500 mum diameter. They are devoid of myelin and are surrounded by a rim of activated microglia intermingled with the C4d-CAOs. Although C4d-immunostained periaxonal oligodendroglial processes are often swollen, the axons of passage appear undamaged and extend through the demyelinated plaque area. No immunostaining with other components of the complement cascade (C1q-C9) was observed in association with these miniature plaques. However, in large MS lesions, C1q-C9 immunoreactive fibers were present, indicating complete activation of the complement cascade in these more developed lesions. It is possible that the miniature plaques, bordered by C4d-CAOs, represent the earliest stage of plaque development, preceding even the larger, transient plaques frequently observed in serial MRI studies. The association of CAOs with miniature areas of demyelination suggests a direct attack on oligodendroglial cells by the early complement components as an initiating event in MS. Incomplete complement activation indicates that this step may be reversible, whereas full and persistent activation as observed in large MS lesions may lead to death of oligodendroglia with permanent axonal damage.

Topics: Aged; Aged, 80 and over; Cerebral Cortex; Complement C4; Complement C4b; Complement System Proteins; Demyelinating Diseases; HLA-DR Antigens; Humans; Immunohistochemistry; Microglia; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Oligodendroglia; Peptide Fragments; Supranuclear Palsy, Progressive