Genetic and sporadic forms of tauopathies—TAU as a disease driver for the majority of patients but the minority of tauopathies

Abstract

Ageing‐associated tauopathies like frontotemporal dementia (FTD), variants thereof (like progressive supranuclear palsy (PSP), pick diseases (PiD), corticobasal degeneration (CBD)), and of course the most prevalent form of dementia, Alzheimer Disease (AD), are widely recognized forms of tauopathies. The list of tauopathies is expanding. We now include: (i) tauopathies where the disease cause or trigger is clearly either physical, such as in Traumatic Brain Injury (TBI) or Chronic Traumatic Encephalopathy (CTE), and (ii) genetic diseases that result in tauopathy but have pathogenic genetic variants in genes not related to TAU. Examples of the latter are myotonic dystrophy Type 1 and Type 2 (DM1, DM2, due to pathogenic genetic variants in the genes DMPK and CNBP, respectively), Niemann–Pick Disease Type C (NPD, due to mutations in NPC1 or NPC2), Kufs Disease (CLN6), Christianson Syndrome (SLC9A6), familial forms of Parkinson Disease (PD), and many others. In terms of affected brain regions and cell types, intracellular distribution of TAU pathology/aggregates, age of disease onset, velocity of disease progression and spreading of TAU pathology, there is, however, little in common in most of these disease entities. Here, I reason that TAU/MAPT is causative for the minority of tauopathies (e.g., MAPT‐related FTD/PSP and Vacuolar Tauopathy (VCP)) and a critical mediator for others, like shown by overwhelming evidence for AD. However, TAU may also be a mere bystander or even protective in other settings. Improved understanding of rare tauopathies is necessary to develop specific treatments, but also to improve our understanding of the pathomechanistic role of TAU and to identify diseases that may profit from TAU‐based therapies.

The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

“…In humans, mutations in MAPT which lead to a loss of its primary function by altering the MT binding affinity or reduce its ability to promote MT assembly, are causative for FTD, but usually also come along with a gain of function, namely increased aggregation propensity. 198 , 203 Furthermore, tauopathies can be classified according to the TAU isoforms present in neuronal inclusions (see also the TAU isoforms in other tauopathies section). In humans, true haploinsufficiency of MAPT alone has not been reported.…”

“…The majority of these diseases occur sporadically, and the underlying triggers remain elusive. 17 However, over 50 variants in MAPT have been associated with FTD (Alzforum database 12/2023), which i.a. lead to imbalances in TAU isoform expression 18 , 19 , 20 , 21 (reviewed, e.g., in 22 , 23 ), clearly demonstrating a pathogenic role of TAU isoforms in at least a subset of FTD.…”

Autoimmune antibody-induced neuronal hyperactivity triggers pathological Tau in IgLON5 disease

“…The discovery of a-IgLON5 disease poses the fundamental questions of whether and how AABs against a cell surface protein can trigger intracellular Tau aggregation and associated pathological changes in the brain. Understanding the mechanisms of how autoimmunity can induce neurodegeneration could not only lead to specific treatment options for a-IgLON5 and further autoantibody-mediated brain diseases, but also provide important insights into how and why pathological Tau changes occur in more than 20 different neurological diseases 10 .…”