Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1

Lazarov, Orly; Morfini, Gerardo; Pigino, Gustavo; Gadadhar, Archana; Chen, Xiangjun; Robinson, John; Ho, Hanson; Brady, Scott T.; Sisodia, Sangram S.

doi:10.1523/jneurosci.4272-06.2007

Cited by 124 publications

(117 citation statements)

References 91 publications

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“…Such an outcome could explain why this organelle has a fragmented and atrophic morphology in neurons of patients with AD. 98 Interestingly, over expression of APOE ε4, as well as mutations in PS1 and APP, also affect tau phosphorylation, axonal transport, and neuronal dystrophy [99][100][101][102] in an Aβ-independent manner, which suggests a possible converging process underlying the familial and sporadic forms of the disease.…”

Section: Early Cytoskeletal Impairmentsmentioning

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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Section: Early Cytoskeletal Impairmentsmentioning

confidence: 99%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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“…Interestingly, HAP1 deficiency also affects kinesin-dependent transport of APP, which suggests a role for HAP1 in the pathogenesis of AD 65 . Mutations in PSEN1 that are associated with FAD deregulate the glycogen synthase kinase-3 ß (Gsk3ß), leading to hyperphosphorylation of Tau and its detachment from microtubules, which results in cytoskeletal collapse and deficits in axonal transport that contribute to the pathogenesis of AD 61,66,67 ( Figure 2). …”

Section: Trafficking Defects In Hd and Ad: Targeting Microtubule-assomentioning

confidence: 99%

“…Reduced BDNF levels 39,40 Increasing BDNF & NGF levels is beneficial in disease models [51][52][53][54] Increased p75 NTR levels and signalling 75,172 Decreased Trk receptor levels and signalling 75,172 Increased Gsk3ß activity 66,173 Altered ERK activity 174 Reduced velocity and efficiency of axonal transport of BDNF 65,66 Apoptotic pathways Increased caspase-6 activity 89,90 Caspase-6 cleavage of disease proteins [89][90][91][92] Preventing caspase cleavage of disease proteins is beneficial in mouse models 93,94 Posttranslational modifications Palmitoylation of disease proteins is linked to aggregate formation 118,119 Phosphorylation of disease proteins reduces their cleavage by caspases 105,106 HDAC inhibition is beneficial in disease models 69,126,127 Protein aggregation and clearance mechanisms Misfolding and aggregation of disease proteins 128 UPS impairment 144,145 Impaired autophagy 161 Upregulation of autophagy is beneficial in disease models 153,155,156,158,162,163,165,167,<...>…”

Section: Supplementary Materialsmentioning

confidence: 99%

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

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Neurodegenerative diseases exemplified by Alzheimer's and Huntington disease are characterized by the progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Even though there are differences in the exact sites of pathology and clinical profiles only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of common therapeutic targets for drug development. Huntington disease with a monogenic cause and the possibility to accurately identify pre-manifest mutation carriers could be exploited as a 'model' for Alzheimer's disease to test the efficacy of therapeutic interventions targeting shared pathogenic pathways.

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“…Retrograde labeling of basal forebrain, after injection of fluorogold into multiple sites in cortex and hippocampus, reveals an altered distribution of phosphotau, GSK3-b, and TrkA immunoreactivity in aged cholinergic neurons (Niewiadomska et al, 2005(Niewiadomska et al, , 2006b. A significant reduction of APP and Trk receptors anterograde fast axonal transport (FAT), in the sciatic nerves from transgenic mice carrying two independent FAD-linked PS1 mutations, is correlated to an increase in GSK-3b-mediated tau phosphorylation in the spinal cord (Lazarov et al, 2007). Recently, an Ab-mediated down-regulation of BDNF retrograde trafficking in AD transgenic mouse neurons (Tg2576) has been reported in correlation with no apparent tau phosphorylation (Tau-1 epitope) modifications (Poon et al, 2009).…”

Section: Ngf and Tau Protein Metabolismmentioning

confidence: 99%

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Calissano

Matrone

Amadoro

2010

Developmental Neurobiology

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Converging lines of evidence on the possible connection between NGF signaling and Alzheimer's diseases (AD) are unraveling new facets which could depict this neurotrophin (NTF) in a more central role. AD animal models have provided evidence that a shortage of NGF supply may induce an AD-like syndrome. In vitro experiments, moreover, are delineating a possible temporal and causal link between APP amiloydogenic processing and altered post-translational tau modifications. After NGF signaling interruption, the pivotal upstream players of the amyloid cascade (APP, b-secretase, and active form of c-secretase) are up-regulated, leading to an increased production of amyloid b peptide (Ab) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Ab released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKb-mediated, phosphorylation at specific pathogenetic sites (Ser262 and Thr 231), caspase(s) and calpain-I-mediated truncation, detachment from microtubules with consequent cytoskeleton collapse and axonal transport impairment. All these events are inhibited when the amyloidogenic processing is reduced by b and c secretase inhibitors or anti-Ab antibodies and appear to be causally correlated to TrkA, p75CTF, Ab, and PS1 molecular association in an Ab-mediated fashion. In this scenario, the so-called trophic action exerted by NGF (and possibly also by other neurotrophins) in these targets neurons is actually the result of an anti-amyloidogenic activity. '

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Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1

Cited by 124 publications

References 91 publications

Deciphering the mechanism underlying late-onset Alzheimer disease

Deciphering the mechanism underlying late-onset Alzheimer disease

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

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