In multiple neurodegenerative diseases, including Alzheimer's disease (AD), a prominent pathological feature is the aberrant aggregation and inclusion formation of the microtubule associated protein tau. Because of the pathological association, these disorders are often referred to as tauopathies. Mutations in the MAPT gene that encodes tau can cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), providing the clearest evidence that the tauopathy plays a causal role in neurodegeneration. However, large gaps in our knowledge remain regarding how various FTDP-17 linked tau mutations promote tau aggregation and neurodegeneration, and more generally how the tauopathy is linked to neurodegeneration. Herein, we review what is known about how FTDP-17-linked pathogenic MAPT mutations cause disease with a major focus on the prion-like properties of wild-type and mutant tau proteins. The hypothesized mechanisms by which mutations in the MAPT gene promote tauopathy are quite varied, and may not provide definitive insights into how tauopathy arises in the absence of mutation. Further, differences in the ability of tau and mutant tau proteins to support prion-like propagation in various model systems raises questions about the generalizability of this mechanism in various tauopathies. Notably, understanding the mechanisms of tauopathy induction and spread and tau-induced neurodegeneration have important implications for tau-targeting therapeutics.

The accumulation of aberrantly aggregated microtubule-associated protein tau (MAPT) 1 defines a spectrum of tauopathies, including Alzheimer's disease. Mutations in the MAPT gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological tau inclusions in the form of neurofibrillary tangles and Pick bodies, and in some cases glial tau pathology. Increasing evidence points to the importance of prion-like seeding as a mechanism for the pathological spread in tauopathy and other neurodegenerative diseases. Herein, using a cell culture model, we examined a multitude of genetic FTDP-17 tau variants for their ability to be seeded by exogenous tau fibrils. Our findings revealed stark differences between FTDP-17 tau variants in their ability to be seeded, with variants at proline 301 and serine 320 showing robust aggregation with seeding. Similarly, we elucidated the importance of certain tau protein regions and unique residues, including the role of proline 301 in inhibiting tau aggregation. We also revealed potential barriers in cross-seeding between 3-repeat and 4-repeat tau isoforms. Overall, these differences alluded to potential mechanistic differences between wild-type and FTDP-17 tau variants, as well as different tau isoforms, in influencing tau aggregation. Furthermore, by combining two FTDP-17 tau variants (either P301L or P301S with S320F), we generated aggressive models of tauopathy that does not require exogenous seeding. These models will allow for rapid screening of potential therapeutics to alleviate tau aggregation without the need for exogenous tau fibrils. Together, these studies provide novel insights in the molecular determinants that modulate tau aggregation.Tauopathies are a spectrum of neurodegenerative diseases characterized by the presence of pathological inclusions composed of aberrantly aggregated and hyperphosphorylated microtubule-associated protein tau (MAPT). Tauopathies are pathologically and phenotypically diverse, and include Alzheimer's disease (AD), progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, Pick's disease, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17)(1-4). Tau is abundant in neurons and expressed at lower levels in glia (1, 6, 7), and primarily stabilizes microtubules (MTs) among other diverse physiological functions (1,5,8,9). Six different isoforms of tau, ranging from 352 to 441 amino acids, are expressed in the adult human brain as a result of alternative splicing (10, 11). Differential splicing results in the inclusion or exclusion of the R2 MT-binding repeat, producing tau isoforms with either three (3R) or four (4R) repeats, respectively, and one or two N-terminal inserts (Figure 1).Over 50 mutations have been identified in the MAPT gene in families with 2,4,12 Tau Mutants and Seeding 2 disease, and patients typically experience disease onset at ~49 years of age with an average disease duration of 8.5 years (13). Certai...

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