Tau seeding in cases of multiple sclerosis

Abstract

Relapsing remitting multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system that in many cases leads to progressive MS, a neurodegenerative disease. Progressive MS is untreatable and relentless, and its cause is unknown. Prior studies of MS have documented neuronal accumulation of phosphorylated tau protein, which characterizes another heterogeneous group of neurogenerative disorders, the tauopathies. Known causes of tauopathy are myriad, and include point mutations within the tau gene, amyloid beta accumulation, repeated head trauma, and viral infection. We and others have proposed that tau has essential features of a prion. It forms intracellular assemblies that can exit a cell, enter a secondary cell, and serve as templates for their own replication in a process termed “seeding.” We have previously developed specialized “biosensor” cell systems to detect and quantify tau seeds in brain tissues. We hypothesized that progressive MS is a tauopathy, potentially triggered by inflammation. We tested for and detected tau seeding in frozen brain tissue of 6/8 subjects with multiple sclerosis. We then evaluated multiple brain regions from a single subject for whom we had detailed clinical history. We observed seeding outside of MS plaques that was enriched by immunopurification with two anti-tau antibodies (HJ8.5 and MD3.1). Immunohistochemistry with AT8 and MD3.1 confirmed prior reports of tau accumulation in MS. Although larger studies are required, our data suggest that progressive MS may be considered a secondary tauopathy.

Pilot Study of the Total and Phosphorylated Tau Proteins in Early-Stage Multiple Sclerosis

“…According to post-mortem studies, tau hyperphosphorylation is found in the brain samples from patients with early aggressive, primary progressive, and secondary progressive MS, whereas the insoluble form is present only in cases of progressive MS [ 54 , 55 , 56 ]. It implies that the accumulation of phospho-tau protein may be the cause of progressive MS and it may be a secondary tauopathy [ 19 ]. In our study, the CSF was collected at the beginning of the disease and the majority of patients showed minimal disability.…”

“…Although this pathological spreading of tau protein, also called seeding, was investigated in detail in tauopathies, mostly Alzheimer’s disease, recently it was also demonstrated in MS patients. LaCroix et al [ 19 ] showed tau seeding in the brain homogenates from six out of eight MS cases, suggesting tau may act as a mediator of neurodegeneration in MS.…”

Cognitive Impairment in Multiple Sclerosis

“…In studies that examine cerebrospinal fluid biomarkers, changes in Aβ 42 as seen in AD can also predict early cognitive decline in MS [173]. Furthermore, the presence of tau seeding, which can lead to AD pathology [37, 98,100,102,105,[174][175][176], has been observed in the brains of patients with MS [177], and tau also may contribute to impaired oligodendrocyte maturation and pathological changes that may foster demyelination [178].…”

Tau, ADNP, and sex

“…Finally, sex differences affect multiple body organs/functions, including, for example, the immune system. An interesting example is multiple sclerosis, an autoimmune disease, presenting tauopathy, being much more prevalent in women than men (LaCroix et al, 2022). Further touching the tip of this iceberg, microglial sex differences link with Tau‐related neurodegenerative diseases (Doust et al, 2021; see also above).…”