{"doi":"10.1111/nan.12792","title":"Classification of diseases with accumulation of Tau protein","abstract":"Abnormal filaments of known composition in neurons and glia define many sporadic and hereditary human neurodegenerative diseases. The pathogenic significance of filamentous inclusions became evident when cases of dominantly inherited disease were shown to be associated with mutations in the genes encoding the proteins that make up filaments, be they Tau [1-3], Aβ [4, 5], α-synuclein [6], prion protein [7], TDP-43 [8-10] or FUS [11, 12]. By extrapolation, it follows that a gain-of-toxic function resulting from the ordered assembly into filaments may also underlie sporadic forms of disease. Assemblies of the microtubule-associated protein Tau into filaments characterise many neurodegenerative diseases. In humans, MAPT, the gene encoding Tau protein, generates six isoforms (352–441 amino acids) by alternative mRNA splicing [13]. They differ by the presence or absence of three inserts encoded by exons 2, 3 and 10. Inclusion of exon 10 results in the production of three isoforms with four C-terminal repeats (each repeat is 31 or 32 amino acids long) (4R) and its exclusion in another three isoforms with three repeats (3R). Diseases characterised by the intracellular accumulation of Tau filaments can be divided into three groups, based on the isoform composition of filaments (3R, 4R, 3R + 4R) [14]. In these diseases, be they sporadic or inherited, Tau is extensively modified post-translationally [15-17]. Tauopathy was coined to describe a dominantly inherited neurodegenerative disease with a +3 mutation in intron 10 of MAPT and abundant filamentous inclusions made of 4R Tau [3, 18]. However, this term is also used in neuropathology and neuroscience to refer to the mere presence of Tau in tissues. The terms primary and secondary tauopathies are also being used [19-25], even though mutations in MAPT are the only known aetiology for Tauopathies. Primary tauopathy refers to conditions where the presence of Tau filaments is the main or sole known abnormality or where tau pathology is considered the major contributing factor to neurodegeneration interpreted as main ‘driving force of pathogenesis’, as opposed to other proteins such as Aβ [23, 25-28]. Primary tauopathies are also included in the group of frontotemporal lobar degeneration (FTLD). The latter is characterised by the predominant atrophy of frontal and temporal lobes of the cerebral cortex and occurs in association with several different proteinopathies [29]. Secondary tauopathy is used when additional ‘driving pathogenic forces’ are believed to be involved [19]. In our view, cases with mutations in MAPT are the only known example of a primary tauopathy, whereas familial Alzheimer's disease may be secondary tauopathy. These terms should not be used when referring to diseases of unknown aetiology. Diseases with pathologic Tau can be classified on the basis Tau isoforms, 3R, 4R or both 3R and 4R being demonstrable with isoform-specific antibodies or Western blot patterns of sarkosyl-insoluble Tau. The anatomical distribution, along with the histological and cytological characterisation of neuronal and glial tau immunoreactivities, is also needed for clinicopathological classification [19, 20, 30]. Formation of abnormal Tau filaments is a central event in several neurodegenerative diseases. Like the filaments of other pathologic amyloids, Tau filaments have a cross-β conformation [31]. Recently, the Tau folds of Alzheimer's disease [32, 33], Pick's disease [34], chronic traumatic encephalopathy (CTE) [35], corticobasal degeneration (CBD) [36, 37], argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) and globular glial tauopathy (GGT) [38] were shown to be different. The Tau filament fold of primary age-related tauopathy (PART) was identical to the Alzheimer fold, indicating that it can form in the absence of Aβ deposits [39]. The same filament structures have been found for different individuals with a given disease. It is also noteworthy that Tau folds identical t","journal":"Neuropathology and Applied Neurobiology","year":2022,"id":234805,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":90,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":268832,"name":"Bernardino Ghetti","orcid":"0000-0002-1842-8019","position":1,"is_corresponding":false},{"id":71017,"name":"Michel Goedert","orcid":"0000-0002-5214-7886","position":2,"is_corresponding":false},{"id":227415,"name":"Gábor G. Kovács","orcid":"0000-0003-3841-5511","position":0,"is_corresponding":true}],"reference_count":147,"raw_metadata":null,"created_at":"2026-07-19T00:21:42.662304Z","pmid":"35064600","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}