Progressive tau aggregation in AD occurs in patterns consistent with neural networks. Additionally, longitudinal tau PET imaging has confirmed the progression of tau pathology along NFT stages, and its correlation with neuronal dysfunction and neurodegeneration. The severity of AD dementia correlates with the extent of postmortem tau pathology. At NFT stages III to IV, more than 50% of individuals have signs of mild cognitive impairment, whereas at NFT stages V and VI more than 90% of individuals exhibit signs of moderate to severe dementia. In NFT stages IV and V, AT8 marks neocortical regions including the superior temporal gyrus (STG), and in NFT stage VI it marks primary neocortical areas such as the visual cortex (VC). In NFT stage III, AT8 marks the CA1 region of the hippocampus, and neocortical regions of the temporal neocortex adjacent to the TRE. In NFT stage II, AT8 marks the entorhinal cortex (EC) in the parahippocampal gyrus. In NFT stage I, AT8 marks selected brainstem nuclei and the transentorhinal cortex (TRE).
AT8 signal increases with disease progression and allows the definition of NFT stages. AT8 binds phospho-serine 202 and phospho-threonine 205 on aggregated tau protein, and marks AD intraneuronal pathology (pretangles and NFTs). Īggregated tau protein is often phosphorylated, and the anti-phospho-tau monoclonal antibody AT8 is typically used for detection and staging. Tau pathology progresses in a defined and characteristic pattern, allowing AD classification into different stages that correlate with antemortem clinical presentation. AD neuropathology includes intraneuronal somatic and axonal pretangles and neurofibrillary tangles (NFTs), neuropil threads (NTs), extraneuronal ghost tangles, and amyloid β plaques. Sporadic Alzheimer’s disease (AD) is the most common, and is uniquely defined by coexistent tau and amyloid β pathology. Tauopathies are a heterogeneous group of neurodegenerative diseases defined by progressive brain accumulation of tau aggregates. The variation in sites of seeding between individuals could underlie differences in the clinical presentation and course of AD. Tau seeding assays reveal pathology in the absence of AT8 signal in some instances, and previously unrecognized sites of tau deposition.
In conclusion, tau histopathology and seeding are complementary analytical tools. We also detected tau seeding in brain regions not previously examined, e.g., the intermediate reticular zone, dorsal raphe nucleus, amygdala, basal nucleus of Meynert, and olfactory bulb. AT8 staining in brain regions identified because of tau seeding also revealed pathology in a previously undescribed cell type: Bergmann glia of the cerebellar cortex. We observed seeding in brain regions not previously known to develop tau pathology, e.g., the globus pallidus and internal capsule, where AT8 staining revealed mainly axonal accumulation of tau. Seeding frequently preceded NFT pathology, e.g., in the basolateral subnucleus of the amygdala and the substantia nigra, pars compacta. We observed a progressive increase in tau seeding according to NFT stage. We measured tau seeding in each of the 500 samples using a cell-based tau “biosensor” assay in which induction of intracellular tau aggregation is mediated by exogenous tau assemblies. We stained and classified 25 brain regions in each using the anti-phospho-tau monoclonal antibody AT8. We selected 20 individuals with AD pathology of NFT stages I, III, and V. We now expand this work to additional regions. Until now, seeding assays of AD brain have largely been limited to areas previously defined by NFT pathology.
This classification is consistent with experimental data which suggests that network-based propagation is mediated by cell–cell transfer of tau “seeds”, or assemblies, that serve as templates for their own replication. The most common tauopathy, sporadic Alzheimer’s disease (AD), involves progressive tau deposition that can be divided into specific stages of neurofibrillary tangle pathology. Tauopathies are heterogeneous neurodegenerative diseases defined by progressive brain accumulation of tau aggregates.
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