Early Axonopathy Preceding Neurofibrillary Tangles in Mutant Tau Transgenic Mice

Leroy, Karelle; Bretteville, Alexis; Schindowski, Katharina; Gilissen, Emmanuel; Authelet, Michèle; Decker, Robert De; Yilmaz, Zehra; Buée, Luc; Brion, Jean Pierre

doi:10.2353/ajpath.2007.070345

Cited by 118 publications

(123 citation statements)

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“…The K3 mice present with earlyonset memory impairment at an age of 4 months, before Bielschowsky-positive tau deposits are detectable. This is in line with the observation that memory deficits precede histopathological changes in other tau-expressing strains (21,42). Pathological tau thus interferes with distinct cellular mechanisms causing neuronal dysfunction before tau is sequestered into deposits.…”

Section: Discussionsupporting

confidence: 88%

Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia

Ittner

Fath

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

209

214

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Frontotemporal dementia (FTD) is characterized by cognitive and behavioral changes and, in a significant subset of patients, Parkinsonism. Histopathologically, FTD frequently presents with taucontaining lesions, which in familial cases result from mutations in the MAPT gene encoding tau. Here we present a novel transgenic mouse strain (K3) that expresses human tau carrying the FTD mutation K369I. K3 mice develop a progressive histopathology that is reminiscent of that in human FTD with the K369I mutation. In addition, K3 mice show early-onset memory impairment and amyotrophy in the absence of overt neurodegeneration. Different from our previously generated tau transgenic strains, the K3 mice express the transgene in the substantia nigra (SN) and show an early-onset motor phenotype that reproduces Parkinsonism with tremor, bradykinesia, abnormal gait, and postural instability. Interestingly, motor performance of young, but not old, K3 mice improves upon L-dopa treatment, which bears similarities to Parkinsonism in FTD. The early-onset symptoms in the K3 mice are mechanistically related to selectively impaired anterograde axonal transport of distinct cargos, which precedes the loss of dopaminergic SN neurons that occurs in aged mice. The impaired axonal transport in SN neurons affects, among others, vesicles containing the dopamine-synthesizing enzyme tyrosine hydroxylase. Distinct modes of transport are also impaired in sciatic nerves, which may explain amyotrophy. Together, the K3 mice are a unique model of FTD-associated Parkinsonism, with pathomechanistic implications for the human pathologic process.tau ͉ Alzheimer ͉ transgenic ͉ NFT ͉ memory H ow neuronal dysfunction and cell loss is brought about in neurodegenerative diseases such as Alzheimer disease (AD) and frontotemporal dementia (FTD) is only partially understood. In familial cases of FTD with tau aggregation (i.e., FTDP-17), mutations were identified in the MAPT encoding the microtubule (MT)-associated protein tau (1), and in FTD cases without tau aggregation, they were identified in PGRN encoding progranulin (2, 3). Of the 42 known MAPT mutations, several have been expressed in transgenic mice. The mice reproduce selective aspects of the disease which is, in part, determined by the choice of promoter and tau isoform, inclusion of FTDP-17 mutations, the integration site, and copy number of the transgene (4).In FTD and AD, tau becomes increasingly hyperphosphorylated, i.e., more phosphorylated at physiological sites and, in addition, de novo at pathological sites (5). Hyperphosphorylation detaches tau from MTs, and makes it prone to form filamentous inclusions, including neurofibrillary tangles (NFTs) in AD and FTD, and Pick bodies in Pick disease (PiD) (6-9). However, it is only partly understood how aggregated tau interferes with cellular functions.Here we report a novel transgenic mouse strain that expresses K369I mutant human tau in neurons (K3 mice). This mutation has been identified in a patient with a PiD neuropathology (10). Different from prev...

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Section: Discussionsupporting

confidence: 88%

Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia

Ittner

Fath

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

209

214

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“…In line with this view, in mice over-expressing mutated human tau, NFT formation is preceded by axonopathy in the absence of amyloid plaque formation. 138 Moreover, genetic ablation of kinesin light chain 1, which induces an age-dependent axonopathy, is accompanied by tau hyperphosphorylation, as evaluated using several AD-specific tau antibodies. 138 …”

Section: Formation Of Neurofibrillary Tanglesmentioning

confidence: 99%

“…138 Moreover, genetic ablation of kinesin light chain 1, which induces an age-dependent axonopathy, is accompanied by tau hyperphosphorylation, as evaluated using several AD-specific tau antibodies. 138 …”

Section: Formation Of Neurofibrillary Tanglesmentioning

confidence: 99%

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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“…inhibited fast axonal transport in isolated axoplasm [41]. Transgenic mice overexpressing human wild-type tau [45] or mutant tau [27] also developed axonal swellings suggestive of defects in axonal transport. In vitro motility assays suggested that tau influences the rate of attachment and detachment of motor proteins along microtubules [15,47].…”

Section: Introductionmentioning

confidence: 99%

Levels of kinesin light chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer’s disease: implications for axoplasmic transport

et al. 2011

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Fast anterograde and retrograde axoplasmic transports in neurons rely on the activity of molecular motors and are critical for maintenance of neuronal and synaptic functions. and DIC in the frontal cortex, but not in the cerebellar cortex, of Alzheimer's disease patients.A significant decrease in the levels of synaptophysin and of tubulin-!3 proteins, two neuronal markers, was also observed. KLC1 and DIC immunoreactivities did not co-localize with neurofibrillary tangles. The mean mRNA levels of KLC1,2 and DIC were not significantly different between controls and AD patients. In SH-SY5Y neural cells, GSK-3! phosphorylated KLC1, a change associated to decreased association of KLC1 with its cargoes. Increased levels of active GSK-3! and of phosphorylated KLC1 were also observed in AD frontal cortex. We suggest that reduction of KLCs and DIC proteins in AD cortex results from both reduced expression and neuronal loss, and that these reductions and GSK-3!-mediated phosphorylation of KLC1 contribute to disturbances of axoplasmic flows and synaptic integrity in Alzheimer's disease.3

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Early Axonopathy Preceding Neurofibrillary Tangles in Mutant Tau Transgenic Mice

Cited by 118 publications

References 74 publications

Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia

Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia

Deciphering the mechanism underlying late-onset Alzheimer disease

Levels of kinesin light chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer’s disease: implications for axoplasmic transport

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