Accumulation of tau induced in neurites by microglial proinflammatory mediators

Gorlovoy, Philipp; Larionov, Sergey; Pham, Thao T. H.; Neumann, Harald

doi:10.1096/fj.08-123877

Cited by 143 publications

(117 citation statements)

References 56 publications

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“…[88][89][90] Similarly, a recent study showed that induced airway allergy in mice modified the brain inflammatory status and increased phosphorylation of tau. 91 Given that phosphorylation of tau is crucial for regulation of microtubule stability and axonal transport, 92 and that hyperphosphorylated tau not only affects the microtubule network but also induces accumulation of filamentous actin and formation of actin-rich rods, 93 these observations could provide a link between inflammatory processes and cytoskeletal abnormalities observed in postmortem examination of all AD cases.…”

Section: Early Cytoskeletal Impairmentsmentioning

confidence: 93%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-(A) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between A and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A accumulation in late-onset AD. Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence ...

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Section: Early Cytoskeletal Impairmentsmentioning

confidence: 93%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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“…Primary microglia and neuronal cells were prepared as described previously (Takahashi et al, 2005;Gorlovoy et al, 2009). Cells were either untreated or treated with 0.5 U/ml endo-N-acetylneuraminidase (EndoN) for 5 h to remove PSA.…”

Section: Methodsmentioning

confidence: 99%

Alleviation of Neurotoxicity by Microglial Human Siglec-11

Wang¹,

Neumann²

2010

J. Neurosci.

159

132

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“…Several mechanisms can be envisaged for this release and re-uptake (e.g., via exosomes; Aguzzi and Rajendran 2009). Alternatively, affected neurons could release factors (e.g., cytokines) that then challenge other neurons, either directly or via intermediate cells; an example is the cytosolic accumulation of Tau in neurons encountering activated microglia or exposed to tumor necrosis factor a (Gorlovoy et al 2009). …”

Section: Tau Protein In Neurofibrillary Degenerationmentioning

confidence: 99%

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Mandelkow

2012

Cold Spring Harbor Perspectives in Medicine

705

636

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Tau represents the subunit protein of one of the major hallmarks of Alzheimer disease (AD), the neurofibrillary tangles, and is therefore of major interest as an indicator of disease mechanisms. Many of the unusual properties of Tau can be explained by its nature as a natively unfolded protein. Examples are the large number of structural conformations and biochemical modifications ( phosphorylation, proteolysis, glycosylation, and others), the multitude of interaction partners (mainly microtubules, but also other cytoskeletal proteins, kinases, and phosphatases, motor proteins, chaperones, and membrane proteins). The pathological aggregation of Tau is counterintuitive, given its high solubility, but can be rationalized by short hydrophobic motifs forming b structures. The aggregation of Tau is toxic in cell and animal models, but can be reversed by suppressing expression or by aggregation inhibitors. This review summarizes some of the structural, biochemical, and cell biological properties of Tau and Tau fibers. Further aspects of Tau as a diagnostic marker and therapeutic target, its involvement in other Tau-based diseases, and its histopathology are covered by other chapters in this volume.

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Accumulation of tau induced in neurites by microglial proinflammatory mediators

Cited by 143 publications

References 56 publications

Deciphering the mechanism underlying late-onset Alzheimer disease

Deciphering the mechanism underlying late-onset Alzheimer disease

Alleviation of Neurotoxicity by Microglial Human Siglec-11

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

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