Abstract
Argyrophilic grain disease (AGD) is a common 4R-tauopathy, causing or contributing to cognitive impairment in the elderly. AGD is characterized neuropathologically by pre-tangles in neurons, dendritic swellings called grains, threads, thorn-shaped astrocytes, and coiled bodies in oligodendrocytes in the limbic system. AGD has a characteristic pattern progressively involving the entorhinal cortex, amygdala, hippocampus, dentate gyrus, presubiculum, subiculum, hypothalamic nuclei, temporal cortex, and neocortex and brainstem, thus suggesting that argyrophilic grain pathology is a natural model of tau propagation. One series of WT mice was unilaterally inoculated in the hippocampus with sarkosyl-insoluble and sarkosyl-soluble fractions from “pure” AGD at the age of 3 or 7/12 months and killed 3 or 7 months later. Abnormal hyper-phosphorylated tau deposits were found in ipsilateral hippocampal neurons, grains (dots) in the hippocampus, and threads, dots and coiled bodies in the fimbria, as well as the ipsilateral and contralateral corpus callosum. The extension of lesions was wider in animals surviving 7 months compared with those surviving 3 months. Astrocytic inclusions were not observed at any time. Tau deposits were mainly composed of 4Rtau, but also 3Rtau. For comparative purposes, another series of WT mice was inoculated with sarkosyl-insoluble fractions from primary age-related tauopathy (PART), a pure neuronal neurofibrillary tangle 3Rtau + 4Rtau tauopathy involving the deep temporal cortex and limbic system. Abnormal hyper-phosphorylated tau deposits were found in neurons in the ipsilateral hippocampus, coiled bodies and threads in the fimbria, and the ipsilateral and contralateral corpus callosum, which extended with time along the anterior-posterior axis and distant regions such as hypothalamic nuclei and nuclei of the septum when comparing mice surviving 7 months with mice surviving 3 months. Astrocytic inclusions were not observed. Tau deposits were mainly composed of 4Rtau and 3Rtau. These results show the capacity for seeding and spreading of AGD tau and PART tau in the brain of WT mouse, and suggest that characteristics of host tau, in addition to those of inoculated tau, are key to identifying commonalities and differences between human tauopathies and corresponding murine models.
Highlights
Tau seeding and spreading occur following unilateral inoculation of sarkosyl-insoluble fractions from Alzheimer’s disease (AD), primary age-related tauopathy (PART), aging-related tau astrogliopathy (ARTAG), progressive supranuclear palsy (PSP), Pick’s disease (PiD), FTLD linked to MAPT P301L mutation, and globular glial tauopathy (GGT) in the hippocampus of WT mice using the protocol utilized in the present study (Ferrer et al, 2018, 2019, 2020a,b)
Neurons and oligodendrocytes are the main targets of tau spreading, which progresses through synaptically connected areas, and along tracts such as the corpus callosum to reach the contralateral hemisphere in those settings
The present results show a similar pattern of tau seeding and spreading following unilateral inoculation of sarkosyl-insoluble fractions from homogenates of Argyrophilic grain disease (AGD) cases without concomitant tauopathy, and more without neurofibrillary tangle (NFT), in the hippocampus of WT mice
Summary
Argyrophilic grain disease (AGD) is a neurodegenerative disorder morphologically characterized by the accumulation of 4R hyper-phosphorylated tau protein in dendritic swellings known as argyrophilic grains, neurons with pre-tangles, coiled bodies in oligodendrocytes, and astrocytes with the morphology of thorn-shaped astrocytes (TSAs), located predominantly in limbic regions of the brain (Braak and Braak, 1987, 1989; Tolnay et al, 1997; Botez et al, 1999; Togo et al, 2002; Zhukareva et al, 2002; Tolnay and Clavaguera, 2004; Ferrer et al, 2008; Tolnay and Probst, 2008; Tolnay and Braak, 2011; Kovacs, 2015; Ikeda et al, 2018; Rösler et al, 2019). AGD stage 1 affects the anterior entorhinal cortex, part of the cortical and basolateral nuclei of the amygdala, and the hypothalamic lateral tuberal nucleus; stage 2 involves a greater number of lesions and progression to the whole entorhinal cortex, anterior CA1, transentorhinal cortex, cortical and basolateral nuclei of the amygdala, presubiculum, hypothalamic lateral tuberal nucleus, and dentate gyrus; stage 3 further involves CA1, perirhinal cortex, presubiculum, amygdala, dentate gyrus, hypothalamic lateral tuberal nucleus, CA2 and CA3, subiculum, other nuclei of the hypothalamus including the mammillary bodies, anterior temporal cortex, insular cortex, anterior cingulated gyrus, orbitofrontal cortex, nucleus accumbens, and septal nuclei; and stage 4 is characterized by further moderate-to-severe involvement of the neocortex and brainstem (Saito et al, 2004; Ferrer et al, 2008; Tolnay and Probst, 2008) This pattern has prompted consideration of argyrophilic grain pathology as a natural model of tau propagation (Clavaguera et al, 2013a; Rábano et al, 2014). Brain extracts from AGD patients have the capacity to transmit tau to HEK293 cells expressing 4Rtau, suggesting that prion-like tau strains can propagate in cultured cells (Woerman et al, 2016)
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