Novel aspects of the phosphorylation and structure of pathological tau: implications for tauopathy biomarkers.

The deposition of highly phosphorylated and aggregated tau is a characteristic of tauopathies, including Alzheimer's disease. It has long been known that different isoforms of tau are aggregated in different cell types and brain regions in each tauopathy. Recent advances in analytical techniques revealed the details of the biochemical and structural biological differences of tau specific to each tauopathy. In this review, we explain recent advances in the analysis of post-translational modifications of tau, particularly phosphorylation, brought about by the development of mass-spectrometry and Phos-tag technology. We then discuss the structure of tau filaments in each tauopathy revealed by the advent of cryo-EM. Finally, we describe the progress in biofluid and imaging biomarkers for tauopathy. This review summarizes current efforts to elucidate the characteristics of pathological tau and the landscape of the use of tau as a biomarker to diagnose and determine the pathological stage of tauopathy.

Mouse Models of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, eventually leading to dementia. The pathological hallmarks of AD are senile plaques and neurofibrillary tangles, which comprise abnormally aggregated ß-amyloid peptide (Aß) and hyperphosphorylated tau protein. To develop preventive, diagnostic, and therapeutic strategies for AD, it is essential to establish animal models that recapitulate the pathophysiological process of AD. In this review, we will summarize the advantages and limitations of various mouse models of AD, including transgenic, knock-in, and injection models based on Aß and tau. We will also discuss other mouse models based on neuroinflammation because recent genetic studies have suggested that microglia are crucial in the pathogenesis of AD. Although each mouse model has its advantages and disadvantages, further research on AD pathobiology will lead to the establishment of more accurate mouse models, and accelerate the development of innovative therapeutics.