title: Neurofibrillary tangles may interfere with Smad 2/3 signaling in neurons.
abstract: Transforming growth factor (TGF)-beta is a multifunctional cytokine with anti-inflammatory, reparative and neuroprotective functions. Increased levels of TGFbeta in Alzheimer disease (AD) are associated with perivascular deposition of extracellular matrix, which may impair clearance of beta-amyloid and contribute to the development of cerebral amyloid angiopathy. TGFbeta signaling is transduced by Smad proteins: on TGFbeta receptor activation, Smads 2 and 3 are released from sequestration by microtubules, phosphorylated (forming pSmad2/3), and, together with Smad 4, translocated to the nucleus, where they initiate the transcription of multiple genes. Neuronal microtubule assembly is disturbed in AD when tau, a microtubule-stabilizing protein, is hyperphosphorylated and forms neurofibrillary tangles. We have investigated the relationship between Ser202 phospho-tau and pSmads 2 and 3 in the temporal lobe in AD. Within neurons in control brains, pSmads 2 and 3 were almost exclusively intranuclear. In AD, pSmad 3 bound to phospho-tau (mostly insoluble tau) and accumulated in the cytoplasm of tangle-bearing neurons; this was accompanied by a marked decrease in nuclear pSmad3. pSmads 2 and 3 were also present in neuronal granulovacuolar inclusions. Our findings suggest that neurofibrillary tangles sequester pSmad3, preventing its translocation into the nucleus and the induction of gene transcription. Interference with the Smad signaling may adversely affect survival of tangle-bearing neurons in AD.
authors.affiliation: Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Department of Clinical Science at North Bristol, Frenchay Hospital, Bristol, UK.
authors.forename: Katy A
authors.initials: KA
authors.lastname: Chalmers
authors.forename: Seth
authors.initials: S
authors.lastname: Love
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D016875:tau Proteins