https://www.cell.com/cell/pdf/S0092-8674(19)31007-4.pdf

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.

In this study, the authors show that microglia play an important role in the propagation of pathogenic tau protein. In addition, the authors find that spread of the tau protein occurs via exosome secretion from these microglial cells.

Depletion of microglia and inhibition of exosome synthesis halt tau propagation

Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer's patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1-42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1-42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer's disease.

/pdf/porphyromonas-gingivalis-in-alzheimer-s-disease-brains-1w9io5d5so.pdf

Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

The pathological assembly of Aβ, tau, and α-synuclein is at the heart of Alzheimer's and Parkinson's diseases. Extracellular deposits of Aβ and intraneuronal tau inclusions define Alzheimer's disease, whereas intracellular inclusions of α-synuclein make up the Lewy pathology of Parkinson's disease. Most cases of disease are sporadic, but some are inherited in a dominant manner. Mutations frequently occur in the genes encoding Aβ, tau, and α-synuclein. Overexpression of these mutant proteins can give rise to disease-associated phenotypes. Protein assembly begins in specific regions of the brain during the process of Alzheimer's and Parkinson's diseases, from where it spreads to other areas.

http://science.sciencemag.org/content/sci/349/6248/1255555.full.pdf

Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein

https://www.cell.com/neuron/pdf/S0896-6273(14)00958-1.pdf

The Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials

Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer’s disease, progressive supranuclear palsy, Pick’s disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as ‘tau propagation’ and may explain the stereotypic progression of tau pathology in the brains of Alzheimer’s disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.

/pdf/a-novel-in-vivo-model-of-tau-propagation-with-rapid-and-19s9sw5xcl.pdf

A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity

Emily McNaughton

Papers

A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity