Impaired hippocampal long-term potentiation in microtubule-associated protein 1B-deficient mice

Zervas, Mark; Opitz, Thoralf; Edelmann, Winfried; Wainer, Bruce H.; Kucherlapati, Raju; Stanton, Patric K.

doi:10.1002/jnr.20624

Cited by 25 publications

(23 citation statements)

References 47 publications

(58 reference statements)

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“…Induced high frequency pre-synaptic stimulation results in prolonged, enhanced post-synaptic sensitivity, presumably correlating with Hebbian learning in synapses. During LTP, MAP1B phosphorylation [21] and local concentrations of mRNA for MAP2 and for Ca 2+ -calmodulin-dependent kinase II (CaMKII) increase [22]. CaMKII is responsible for phosphorylating MAP2, enhancing synaptic response [23].…”

Section: Introductionmentioning

confidence: 99%

The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

et al. 2012

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Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.

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Section: Introductionmentioning

confidence: 99%

The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

et al. 2012

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“…Moreover, TEM data showed a significant increase in the distance of docked vesicles to the base of the T-bar. Knowing that voltagedependent Ca 2ϩ channels are concentrated at this place , and that the extent of the Ca 2ϩ influx depends on the extracellular Ca 2ϩ concentration (Oheim et al, 2006;Thanawala and Regehr, 2013), it is possible that distant docked synaptic vesicles in futsch mutants are less easily reached by the Ca 2ϩ influx. This could explain the reduced release observed in low Ca 2ϩ concentrations in futsch mutants.…”

Section: Discussionmentioning

confidence: 99%

“…All MAP1 proteins play a role in MT stabilization, and their transfection in heterologous cell systems induces the formation of MT bundles (Noiges et al, 2002). MAP1B knock-out mice revealed the developmental functions of the MAP1 family: MAP1B is involved in axonal branching and guidance, neurite growth or growth cone function (González et al, 2000;Meixner et al, 2000;Takei et al, 2000;González-Billault et al, 2001Bouquet et al, 2004;Montenegro-Venegas et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…These interactions with channels or receptors suggest a potential role of MAP1 proteins in neuronal communication by linking these proteins to MTs. A number of studies have focused on MAP1 proteins at the postsynapse (Trotta et al, 2004;Pangratz-Fuehrer et al, 2005;Zervas et al, 2005;Tortosa et al, 2011). However, presynaptic roles of MAP1 proteins are poorly studied: do MAP1 proteins play a role in neurotransmitter release and do they interact with components of the synaptic release machinery?…”

Section: Introductionmentioning

confidence: 99%

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A Presynaptic Role of Microtubule-Associated Protein 1/Futsch inDrosophila: Regulation of Active Zone Number and Neurotransmitter Release

et al. 2014

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Structural microtubule-associated proteins (MAPs), like MAP1, not only control the stability of microtubules, but also interact with postsynaptic proteins in the nervous system. Their presynaptic role has barely been studied. To tackle this question, we used the Drosophila model in which there is only one MAP1 homolog: Futsch, which is expressed at the larval neuromuscular junction, presynaptically only. We show that Futsch regulates neurotransmitter release and active zone density. Importantly, we provide evidence that this role of Futsch is not just the consequence of its microtubule-stabilizing function. Using high-resolution microscopy, we show that Futsch and microtubules are almost systematically present in close proximity to active zones, with Futsch being localized in-between microtubules and active zones. Using proximity ligation assays, we further demonstrate the proximity of Futsch, but not microtubules, to active zone components. Altogether our data are in favor of a model by which Futsch locally stabilizes active zones, by reinforcing their link with the underlying microtubule cytoskeleton.

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“…MAP1B in the cortex has been strongly implicated in synapse formation and function (Kawakami et al, 2003). Such a role has been recently functionally demonstrated through the observation that mice lacking the phosphorylated form of MAP1B specifically in the hippocampus, show deficits in longterm potentiation in the Schaeffer collaterals pathway (Zervas et al, 2005). Therefore, it is conceivable that MAP1B is implicated in the positioning and transport of BAD-LAMP vesicles at sites of postsynaptic densities on the dendrites of cortical neurons, and that this process could be essential for stabilization, function and plasticity of cortical synapses.…”

Section: Discussionmentioning

confidence: 99%

BAD-LAMP defines a subset of early endocytic organelles in subpopulations of cortical projection neurons

David

Tiveron

Defays

et al. 2007

Journal of Cell Science

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The brain-associated LAMP-like molecule (BAD-LAMP) is a new member of the family of lysosome associated membrane proteins (LAMPs). In contrast to other LAMPs, which show a widespread expression, BAD-LAMP expression in mice is confined to the postnatal brain and therein to neuronal subpopulations in layers II/III and V of the neocortex. Onset of expression strictly parallels cortical synaptogenesis. In cortical neurons, the protein is found in defined clustered vesicles, which accumulate along neurites where it localizes with phosphorylated epitopes of neurofilament H. In primary neurons, BAD-LAMP is endocytosed, but is not found in classical lysosomal/endosomal compartments. Modification of BAD-LAMP by addition of GFP revealed a cryptic lysosomal retention motif, suggesting that the cytoplasmic tail of BAD-LAMP is actively interacting with, or modified by, molecules that promote its sorting away from lysosomes. Analysis of BAD-LAMP endocytosis in transfected HeLa cells provided evidence that the protein recycles to the plasma membrane through a dynamin/AP2-dependent mechanism. Thus, BAD-LAMP is an unconventional LAMP-like molecule and defines a new endocytic compartment in specific subtypes of cortical projection neurons. The striking correlation between the appearance of BAD-LAMP and cortical synatogenesis points towards a physiological role of this vesicular determinant for neuronal function.

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Impaired hippocampal long-term potentiation in microtubule-associated protein 1B-deficient mice

Cited by 25 publications

References 47 publications

The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

A Presynaptic Role of Microtubule-Associated Protein 1/Futsch inDrosophila: Regulation of Active Zone Number and Neurotransmitter Release

BAD-LAMP defines a subset of early endocytic organelles in subpopulations of cortical projection neurons

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