Effects of P301L-TAU on post-translational modifications of microtubules in human iPSC-derived cortical neurons and TAU transgenic mice

TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.

Amyloid-β-induced disruption of axon-initial-segment mitochondria localization:consequences for TAU missorting in Alzheimer's disease pathology

TAU is a neuronal microtubule-associated protein preferentially located in axons.In a battery of neurodegenerative diseases termed"tauopathies,"including Alzheimer's disease (AD),TAU is missorted and abnormally phosphorylated,leading to filamentous accumulations of hyperphosphorylated TAU,a pathological hallmark and potential disease driver of AD and related tauopathies (Zempel,2024).

Suppression of mature TAU isoforms prevents Alzheimer's disease-like amyloid-beta oligomer-induced spine loss in rodent neurons

Introduction:TAU isoforms as disease mediators:The microtubule-associated protein TAU is predominantly present in the axons of neurons under physiological conditions.In Alzheimer’s disease(AD)and related tauopathies,TAU also mislocalizes("TAU missorting")to the soma and the dendrites,where it eventually forms aggregates,the so-called neurofibrillary tangles(for review see Zimmer-Bensch and Zempel,2021;Zempel,2023).

A simple human cell model for TAU trafficking and tauopathy-related TAU pathology

The microtubule(MT)-associated protein TAU is highly abundant in the axon of human brain neurons,where it binds to and stabilizes MT filaments.Thereby,TAU regulates the dynamic(dis)assembly of MT strands and is involved in a wide range of neuronal functions.In Alzheimer's disease(AD)and other tauopathies,TAU is missorted into the somatodendritic compartment.TAU missorting is accompanied by(or leads to)abnormal TAU phosphorylation,MT destabilization,and loss of dendritic spines and mitochondria,eventually resulting in TAU aggregation,neuronal dysfunction and cell death(Arendt et al.,2016).Strikingly,the mechanisms of TAU sorting,and the detrimental cascade upon its failure,are still not fully understood.

AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

Tauopathies comprise a spectrum of genetic and sporadic neurodegenerative diseases mainly characterized by the presence of hyperphosphorylated TAU protein aggregations in neurons or glia.Gene therapy,in particular adeno-associated virus(AAV)-based,is an effective medical approach for difficult-to-treat genetic diseases for which there are no convincing traditional therapies,such as tauopathies.Employing AAV-based gene therapy to treat,in particular,genetic tauopathies has many potential therapeutic benefits,but also drawbacks which need to be addressed in order to successfully and efficiently adapt this still unconventional therapy for the various types of tauopathies.In this Viewpoint,we briefly introduce some potentially treatable tauopathies,classify them according to their etiology,and discuss the potential advantages and possible problems of AAV-based gene therapy.Finally,we outline a future vision for the application of this promising therapeutic approach for genetic and sporadic tauopathies.

Microtubule affinity regulating kinase(MARK/Par1)isoforms differentially regulate Alzheimer-like TAU missorting and Aβ-mediated synapse pathology

Importance of TAU protein for dementia syndromes:Dementia currently affects about 55 million people worldwide,with Alzheimer's disease(AD)being the most prevalent form.The one crucial pathological hallmark of AD that correlates best with loss of synapses and cognitive decline are the so-called intracellular neurofibrillary tangles composed of mislocalized/missorted and hyperphosphorylated TAU protein(Naseri et al.,2019).Many other neurodegenerative diseases,both genetic and nongenetic,are characterized by neurofibrillary ta ngles or pathological accumulation of the protein TAU and are thus termed"tauopathies".

Understanding genetics, sex and signaling: Implications of sex-dependent APOE4-neutrophil-microglia interactions for Alzheimer’s and tauopathies

A recent study published in Nature Medicine uncovers a novel sex-dependent mechanism involving the apolipoprotein E ε4 (APOE4) and in particular neutrophils and their signaling to microglia, which then would mediate cognitive decline in late-onset Alzheimer’s disease (AD).1 We here put the main findings into perspective with current knowledge about APOE4 genotype and neutrophils in the pathogenesis of AD and related tauopathies, and discuss future research directions and therapeutic implications.

Persistent astrocytic IL-3 stimulation of microglia slows disease in Alzheimer’s:treatment perspectives for Alzheimer’s

In their new paper,McAlpine and colleagues provide compelling evidence that astrocyte dependent microglial stimulation is crucial for fighting off one of the most prominent Alzheimer disease(AD)pathological hallmarks,namelyβ-amyloid(Aβ)plaque deposition.They find that(i)a subpopulation of astrocytes secrete the classical cytokine interleukin-3(IL-3),(ii)microglia are responsive to this cytokine,(iii)responsiveness(not so much secretion of IL-3)is increased in patients with AD and model systems of AD,and(iv)presence of IL-3 is necessary to allow microglia to counteract some of the detrimental effects of AD:if IL-3 is missing,AD pathology worsens(see Fig.1 for graphical depiction).1 AD and related tauopathies,e.g.,frontotemporal dementia(FTD)or frontotemporal lobar degeneration with tauopathy(FTLDTAU),are detrimental diseases,impose a huge burden on patients and caregivers,and are the scourge of modern healthcare systems.Despite recent advances in(immuno-)therapies,a causative cure seems out of range.