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Alzheimer Disease ll: Pathophysiology

Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and microglia. Abnormal...
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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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Published on: January 2, 2015

TDP-43 dysfunction facilitates the pathological conversion of tau.

Meghraj S Baghel1, Grace D Burns1, Margarita Tsapatsis1

  • 1Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.

Molecular Neurodegeneration
|July 4, 2026
PubMed
Summary

TDP-43 dysfunction worsens neurodegeneration in Alzheimer's Disease (AD) and related dementias. Loss of TDP-43 function promotes tau cleavage by caspase 3, accelerating brain atrophy and neuron loss in tauopathy.

Keywords:
ADRDAlzheimer’s diseaseCaspaseCo-pathologyFTDMouse modelNeurodegenerationTDP-43TauTauopathyVulnerable neuron

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Area of Science:

  • Neurobiology
  • Molecular Biology
  • Neurodegenerative Diseases

Background:

  • TDP-43 proteinopathy and tauopathy often coexist in neurodegenerative disorders like Alzheimer's Disease (AD) and AD-related dementia (ADRD).
  • The co-pathology of TDP-43 is linked to increased neurodegeneration, but the underlying mechanisms driving neuron loss are not fully understood.
  • Loss of TDP-43's splicing repression function early in neurodegenerative disease may promote the pathological transformation of tau.

Purpose of the Study:

  • To investigate how TDP-43 loss-of-function (LOF) influences tauopathy and exacerbates neurodegeneration.
  • To elucidate the role of caspase 3-dependent tau cleavage in TDP-43-associated neurodegeneration.
  • To identify potential therapeutic targets for tauopathies with co-occurring TDP-43 pathology.

Main Methods:

  • Utilized a mouse model (Tau4R; CaMKII-CreER; Tardbpf/f) with TDP-43 LOF in forebrain neurons.
  • Investigated TDP-43 LOF effects on tauopathy and neuronal vulnerability using caspase 3 cleavage assays.
  • Employed human induced pluripotent stem cell (iPSC)-derived cortical neurons to study TDP-43 LOF-induced cryptic splicing and tau cleavage.
  • Genetically induced tauopathy in mice to assess the correlation between tau seeding, tau cleavage, and neurodegeneration.

Main Results:

  • TDP-43 LOF in forebrain neurons exacerbates tauopathy-dependent brain atrophy, linked to caspase 3-dependent cleavage of tau in vulnerable neurons.
  • TDP-43 LOF in human iPSC-derived neurons promotes TDP-43-dependent cryptic splicing, preceding caspase 3-mediated tau endoproteolysis.
  • In mice, tau seeding correlated with increased caspase 3-dependent tau cleavage, accelerated tauopathy, and loss of TDP-43-deficient neurons.

Conclusions:

  • TDP-43 dysfunction exacerbates tauopathy-driven brain atrophy by promoting caspase 3-dependent tau endoproteolysis.
  • These findings reveal novel mechanistic insights into the interplay between TDP-43 and tau pathology.
  • The study highlights caspase 3-dependent tau cleavage as a potential therapeutic target for tauopathies with co-pathology.