Amyloid-β plaques disrupt axon initial segments

Marin, Miguel A.; Ziburkus, Jokubus; Jankowsky, Joanna L.; Rasband, Matthew N.

doi:10.1016/j.expneurol.2016.04.018

Cited by 56 publications

(43 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5j , upper panel). Moreover, AIS shortening represents a remarkable neuronal alteration detected in murine models of Alzheimer 40 , 41 , in which the expression of exogenous AnkG improves their cognitive performance 42 . Considering that the G1/S regulator Cdk2 can phosphorylate the Kvβ2 auxiliary subunit of the Kv1 channel 43 , it is conceivable that an obstruction in the targeting of the Kv1 channel in the AIS could be occurring, which may also alter spike firing 44 .…”

Section: Discussionmentioning

confidence: 99%

Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in differentiated cortical neurons

Barrio-Alonso

Hernández‐Vivanco

Walton

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Cell cycle reentry followed by neuronal hyperploidy and synaptic failure are two early hallmarks of Alzheimer’s disease (AD), however their functional connection remains unexplored. To address this question, we induced cell cycle reentry in cultured cortical neurons by expressing SV40 large T antigen. Cell cycle reentry was followed by hyperploidy in ~70% of cortical neurons, and led to progressive axon initial segment loss and reduced density of dendritic PSD-95 puncta, which correlated with diminished spike generation and reduced spontaneous synaptic activity. This manipulation also resulted in delayed cell death, as previously observed in AD-affected hyperploid neurons. Membrane depolarization by high extracellular potassium maintained PSD-95 puncta density and partially rescued both spontaneous synaptic activity and cell death, while spike generation remained blocked. This suggests that AD-associated hyperploid neurons can be sustained in vivo if integrated in active neuronal circuits whilst promoting synaptic dysfunction. Thus, cell cycle reentry might contribute to cognitive impairment in early stages of AD and neuronal death susceptibility at late stages.

show abstract

Section: Discussionmentioning

confidence: 99%

Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in differentiated cortical neurons

Barrio-Alonso

Hernández‐Vivanco

Walton

et al. 2018

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Interestingly, hyperphosphorylated tau in primary cultured neurons and mutant tau transgenic mice induced a distal shift of the AIS, which was associated with reduced excitability of neurons (Hatch et al, 2017). Furthermore, oligomeric Ab disrupts integrity of the AIS (Marin et al, 2016;Tsushima et al, 2015), contributing to the loss of tau polarization seen in AD neurons.…”

Section: Polarized Neuronal Distribution Of Taumentioning

confidence: 99%

Dendritic Tau in Alzheimer’s Disease

Ittner

2018

Neuron

201

199

View full text Add to dashboard Cite

The microtubule-associated protein tau and amyloid-β (Aβ) are key players in Alzheimer's disease (AD). Aβ and tau are linked in a molecular pathway at the post-synapse with tau-dependent synaptic dysfunction being a major pathomechanism in AD. Recent work on site-specific modification of dendritic and more specifically post-synaptic tau has revealed new endogenous functions of tau that limits synaptic Aβ toxicity. Thus, molecular studies opened a new perspective on tau, placing it at the center of neurotoxic and neuroprotective signaling at the post-synapse. Here, we review recent advances on tau in the dendritic compartments, with implications for understanding and treatment of AD and related neurological conditions.

show abstract

“…Remarkably, during development of tauopathies such as Alzheimer's disease (AD), tau redistributes from the axon to the somatodendritic compartment, where it aggregates into filamentous structures (paired or straight helical filaments), which form neurofibrillary tangles (6). The enrichment of tau in the axon may at least partially be mediated by the axon initial segment (AIS), which is thought to act as a selective diffusion barrier for various proteins (7)(8)(9) In fact, the integrity of the AIS is disrupted in animal models of AD (10), which may contribute to the pathologic mislocalization of tau during disease. However, it is still a matter of debate how tau becomes enriched in the axon, how it is retained in this compartment, and what causes its redistribution during disease.…”

mentioning

confidence: 99%

Annexins A2 and A6 interact with the extreme N terminus of tau and thereby contribute to tau's axonal localization

Gauthier-Kemper

Alonso

Sündermann

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

During neuronal development, the microtubule-associated protein tau becomes enriched in the axon, where it remains concentrated in the healthy brain. In tauopathies such as Alzheimer's disease, tau redistributes from the axon to the somatodendritic compartment. However, the cellular mechanism that regulates tau's localization remains unclear. We report here that tau interacts with the Ca-regulated plasma membrane-binding protein annexin A2 (AnxA2) via tau's extreme N terminus encoded by the first exon (E1). Bioinformatics analysis identified two conserved eight-amino-acids-long motifs within E1 in mammals. Using a heterologous yeast system, we found that disease-related mutations and pseudophosphorylation of Tyr-18, located within E1 but outside of the two conserved regions, do not influence tau's interaction with AnxA2. We further observed that tau interacts with the core domain of AnxA2 in a Ca-induced open conformation and interacts also with AnxA6. Moreover, lack of E1 moderately increased tau's association rate to microtubules, consistent with the supposition that the presence of the tau-annexin interaction reduces the availability of tau to interact with microtubules. Of note, intracellular competition through overexpression of E1-containing constructs reduced tau's axonal enrichment in primary neurons. Our results suggest that the E1-mediated tau-annexin interaction contributes to the enrichment of tau in the axon and is involved in its redistribution in pathological conditions.

show abstract

Amyloid-β plaques disrupt axon initial segments

Cited by 56 publications

References 24 publications

Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in differentiated cortical neurons

Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in differentiated cortical neurons

Dendritic Tau in Alzheimer’s Disease

Annexins A2 and A6 interact with the extreme N terminus of tau and thereby contribute to tau's axonal localization

Contact Info

Product

Resources

About