Molecular polymorphism of tau aggregates in Pick's disease

Tau protein is central to progressive neuropathological changes in many neurodegenerative diseases. Although the trajectory by which tau pathology spreads through neural networks has been studied, the molecular processes that drive disease are unknown. Characterizing these processes requires imaging tools that supplement neuropathological examination with information about the molecular organization of lesions while preserving details of their anatomical location. High-resolution cryo-electron microscope studies require isolation of material which destroys information on variation of lesion structure with location. Immunohistochemistry identifies principal constituents of lesions but provides little information about molecular organization. To bridge this knowledge gap, we have developed advanced biophysical imaging tools to probe, in situ, the molecular organization and composition of individual lesions within diseased brain tissue. Here we describe their use to assess the fibrillar organization and variation of elemental composition in tau-containing lesions within the brain of a 66-year-old male with dementia.

We used in situ micro X-ray diffraction (μXRD) to determine the aggregation state of tau in individual lesions and micro-X-ray fluorescence (μXRF) to determine the elemental content of these lesions. The information thus generated was combined with immunohistochemistry of serial sections that confirmed the principal molecular constituents of lesions and placed the results in a broader anatomical context.

Neuropathological examination revealed classical forms of tau inclusions in the hippocampal formation including extensive Pick bodies in the dentate gyrus. μXRD data indicate that Pick bodies of the granular layer are relatively low in fibril content, whereas, surprisingly, the microscopically diffuse tau in the neuropil in adjacent CA4 and hilus regions exhibit far greater density of fibrillar signal. μXRF data show elevated levels of zinc, calcium and phosphorous relative to surrounding tissue in essentially all tau-containing lesions. Sulfur deposition appeared greater in areas exhibiting high fibrillar content. A second case of Pick's disease showed analogous results.

These observations demonstrate a correlation of lesion morphology with anatomical localization, degree of tau fibrillation and differential accumulation of metals and suggest that lesions containing different levels of tau fibrils harbor biochemically distinct microenvironments.