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It has been proposed that tau aggregation confined to entorhinal cortex and hippocampus, with no or only minimal Aβ deposition, should be considered as a ‘primary age-related tauopathy’ (PART) that is not integral to the continuum of sporadic Alzheimer disease (AD). Here, we examine the evidence that PART has a pathogenic mechanism and a prognosis which differ from those of AD. We contend that no specific property of the entorhinal–hippocampal tau pathology makes it possible to predict either a limited progression or the development of AD, and that biochemical differences await an evidence base. On the other hand, entorhinal–hippocampal tau pathology is an invariant feature of AD and is always associated with its development. Rather than creating a separate disease entity, we recommend the continued use of an analytical approach based on NFT stages and Aβ phases with no inference about hypothetical disease processes.

Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene MAPT . Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when MAPT mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. MAPT -associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies.

INTRODUCTION Alternative splicing of the human MAPT gene generates six brain‐specific TAU isoforms. Imbalances in the TAU isoform ratio can lead to neurodegenerative diseases, underscoring the need for precise control over TAU isoform balance. Tauopathies, characterized by intracellular aggregates of hyperphosphorylated TAU, exhibit extensive neurodegeneration and can be classified by the TAU isoforms present in pathological accumulations. METHODS A comprehensive review of TAU and related dementia syndromes literature was conducted using PubMed, Google Scholar, and preprint server. RESULTS While TAU is recognized as key driver of neurodegeneration in specific tauopathies, the contribution of the isoforms to neuronal function and disease development remains largely elusive. DISCUSSION In this review we describe the role of TAU isoforms in health and disease, and stress the importance of comprehending and studying TAU isoforms in both, physiological and pathological context, in order to develop targeted therapeutic interventions for TAU‐associated diseases. Highlights MAPT splicing is tightly regulated during neuronal maturation and throughout life. TAU isoform expression is development‐, cell‐type and brain region specific. The contribution of TAU to neurodegeneration might be isoform‐specific. Ineffective TAU‐based therapies highlight the need for specific targeting strategies.

Microtubule-associated protein tau is abnormally aggregated in neuronal and glial cells in a range of neurodegenerative diseases that are collectively referred to as tauopathies. Multiple studies have suggested that pathological tau species may act as a seed that promotes aggregation of endogenous tau in naïve cells and contributes to propagation of tau pathology. While they share pathological tau aggregation as a common feature, tauopathies are distinct from one another with respect to predominant tau isoforms that accumulate and the selective vulnerability of brain regions and cell types that have tau inclusions. For instance, primary tauopathies present with glial tau pathology, while it is mostly neuronal in Alzheimer’s disease (AD). Also, morphologies of tau inclusions can greatly vary even within the same cell type, suggesting distinct mechanisms or distinct tau conformers in each tauopathy. Neuropathological heterogeneity across tauopathies challenges our understanding of pathophysiology behind tau seeding and aggregation, as well as our efforts to develop effective therapeutic strategies for AD and other tauopathies. In this review, we describe diverse neuropathological features of tau inclusions in neurodegenerative tauopathies and discuss what has been learned from experimental studies with mouse models, advanced transcriptomics, and cryo-electron microscopy (cryo-EM) on the biology underlying cell type-specific tau pathology.

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer’s disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro , neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term ‘cistauosis’, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer’s disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury. Here the cis form of tau protein, which disrupts axonal microtubules and transport, spreads to other neurons, and leads to apoptosis in vitro and in vivo , is found to be produced by neurons immediately after traumatic brain injury (TBI); treating TBI mice with cis antibody blocks early production of cis tau, prevents tauopathy and spread and restores brain structural and functional outcomes, and may be further developed to treat TBI and to prevent neurodegeneration after injury. cis P-tau tauopathy in traumatic brain injury The symptoms of traumatic brain injury (TBI), a common condition in players of contact sports and in the military, are associated with acute neurological dysfunction and TBI is a major risk factor for Alzheimer's disease. Tauopathy associated with the aggregation of phosphorylated tau protein (P-tau) in the brain is a defining feature of the neurodegeneration associated with chronic traumatic encephalopathy and Alzheimer's but it has not been observed in the early stages of TBI. Here Kun Ping Lu and colleagues show that tauopathy caused by cis P-tau, but not trans P-tau, is an early driver of brain injury in patients with TBI and in mouse models. Treating TBI mice with cis antibody blocks early production of cis P-tau and prevents further tauopathy and spread, and may be further developed to treat TBI after injury.

Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression. The tau protein has been implicated in neurodegenerative disorders and can propagate from cell to cell. Here, the authors show that tau acetylation reduces its degradation by chaperone-mediated autophagy, causing re-routing to other autophagic pathways and increasing extracellular tau release.

ApoE4 exacerbates tau pathogenesis, neuroinflammation and tau-mediated neurodegeneration independently of brain amyloid-β pathology, and exerts a ‘toxic’ gain of function whereas its absence is protective. Alzheimer's risk factor aggravates tau pathology APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology compared to other ApoE isoforms. However, whether APOE independently influences tau pathology is not clear. David Holtzman and colleagues now show that ApoE4 exacerbates tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independent of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function, whereas the absence of ApoE is protective. APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms 1 . However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro , E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4 -carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.

In AD research, word-learning tests are often used interchangeably despite using distinct learning protocols. This study verified the equivalence of the Rey Auditory Learning Test (RAVLT) and Free and Cued Selective Reminding Test (FCSRT) when investigating medial temporal lobe (MTL) changes and AD-related tau pathology. We obtained the FCSRT and RAVLT immediate and delayed free recalls from 286 participants aged 51+. We segmented MTL regions to obtain the volume and tau-PET signal using the [ 18 F]MK-6240 tracer. Tau-PET Braak stages and plasma p-tau 181 , p-tau 217 and p-tau 231 quantifications were also acquired. Using partial correlations, we compared FCSRT to RAVLT as well as their ability to detect the cognitive status the AD biomarker results. FCSRT and RAVLT were strongly correlated to one another ( R  > 0.779), with similar differentiation of cognitively impaired and cognitively unimpaired individuals (AUC > 0.810). Both predicted MTL volume, MTL tau-PET accumulation, plasma p-tau and Braak stages similarly, with no significant effect size differences. For all tests, a subtle memory impairment was found at tau-PET Braak stage III, while more robust impairments were found at stage IV onward. Despite their differences, both the RAVLT and FCSRT are equivalent at detecting AD-related pathology and symptoms, suggesting that, in these contexts, they may be used interchangeably. However, these results should be interpreted with care since the sample is not representative of a global population.

We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define “definite”, “probable” and “possible” diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A “definite” diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a “probable” diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A “possible” diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder.