Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy

Abstract

Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in MAPT and one case of sporadic GGT (sGGT) and one case of GGT linked to MAPT K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to MAPT P301T mutation, astrocyte markers GFAP, ALDH1L1, YKL40 mRNA and protein, GJA1 mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers OLIG1 and OLIG2 mRNA, and myelin-related genes MBP, PLP1, CNP, MAG, MAL, MOG, and MOBP are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to MAPT K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to MAPT P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to MAPT P301T, sGGT, and GGT linked to MAPT K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time-and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates. Keywords Globular glial tauopathy • Tau • Astrogliopathy • Oligodendrogliopathy • Phosphoproteome • Seeding and spreading alien hand, myoclonus, and dystonic movements...

Capacity for Seeding and Spreading of Argyrophilic Grain Disease in a Wild-Type Murine Model; Comparisons With Primary Age-Related Tauopathy

“…Localization of phospho-tau in neurons and oligodendrocytes in AGD-inoculated mice was identified with double-labeling immunofluorescence with anti-phospho-tau antibodies in combination with NeuN and Olig2 antibodies, respectively ( Figures 7A–C ). Antibodies anti-p38-P (Thr180-Tyr182) revealed co-localization with phospho-tau (AT8) in the majority of grains or dots ( Figure 7D ), as well as in pre-tangles and coiled bodies, as detailed in other tauopathies ( Ferrer et al, 2018 , 2019 , 2020a ).…”

“…Tau seeding and spreading occur following unilateral inoculation of sarkosyl-insoluble fractions from AD, PART, ARTAG, PSP, PiD, FTLD linked to MAPT P301L mutation, and 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.…”

“…Endogenous mouse tau is accumulated in oligodendrocytes in mice expressing transgenic human tau, thus indicating that mouse tau has the capacity to be recruited and aggregated in oligodendrocytes ( Ren et al, 2014 ). Moreover, oligodendrocytes are the only cell targets, beside threads, following inoculation of sarkosyl-insoluble fractions from a wide variety of tauopathies in the corpus callosum of WT mice ( Ferrer et al, 2018 , 2019 , 2020a , b ). Similarly, human tau can be trapped by axons following inoculation.…”

“…Our previous studies have shown tau seeding and spreading following inoculation of sarkosyl-insoluble fractions from AD, primary age-related tauopathy (PART), aging-related tau astrogliopathy (ARTAG), progressive supranuclear palsy (PSP), Pick’s disease (PiD), frontotemporal lobar degeneration linked to MAPT P301L mutation, and sporadic and familial globular glial tauopathy (GGT) into the hippocampus and corpus callosum of WT mice ( Ferrer et al, 2018 , 2019 , 2020a , b ). The present study is focused on the capacity for and characteristics of seeding and propagation of phospho-tau from homogenates of “pure” (not associated with AD or other tauopathies) AGD cases in the hippocampus of WT mice.…”

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

“…Whilst many studies focus on neuronal damage, white matter hyperintensities (evidence of demyelination) are commonly reported in the early stages of AD and other tauopathies and correlate with tau burden [173]. A recent study describes human familial globular glial tauopathy, linked to MAPT mutations, that result in extensive tau deposits in oligodendrocytes [73]. Affected individuals show severe demyelination, defective myelin synthesis, and concomitant axonal damage [73].…”