The Calcium-Binding Protein EFhd2 Modulates Synapse Formation In Vitro and Is Linked to Human Dementia

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EFhd2 is a calcium-binding adaptor protein that has been found to be associated with pathologically aggregated tau in the brain in Alzheimer disease and in a mouse model of frontotemporal dementia. EFhd2 has cell type–specific functions, including the modulation of intracellular calcium responses, actin dynamics, and microtubule transport. Here we report that EFhd2 protein and mRNA levels are reduced in human frontal cortex tissue affected by different types of dementia with and without tau pathology. We show that EFhd2 is mainly a neuronal protein in the brain and is abundant in the forebrain. Using short hairpin RNA–mediated knockdown of EFhd2 expression in cultured cortical neurons, we demonstrate that loss of EFhd2 affects the number of synapses developed in vitro whereas it does not alter neurite outgrowth per se. Our data suggest that EFhd2 is involved in the control of synapse development and maintenance through means other than affecting neurite development. The changes in expression levels observed in human dementias might, therefore, play a significant role in disease onset and progression of dementia, which is characterized by the loss of synapses.

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Classification and basic pathology of Alzheimer disease.

Charles Duyckaerts, Benoît Delatour, Marie-Claude Potier (2009)

The lesions of Alzheimer disease include accumulation of proteins, losses of neurons and synapses, and alterations related to reactive processes. Extracellular Abeta accumulation occurs in the parenchyma as diffuse, focal or stellate deposits. It may involve the vessel walls of arteries, veins and capillaries. The cases in which the capillary vessel walls are affected have a higher probability of having one or two apoepsilon 4 alleles. Parenchymal as well as vascular Abeta deposition follows a stepwise progression. Tau accumulation, probably the best histopathological correlate of the clinical symptoms, takes three aspects: in the cell body of the neuron as neurofibrillary tangle, in the dendrites as neuropil threads, and in the axons forming the senile plaque neuritic corona. The progression of tau pathology is stepwise and stereotyped from the entorhinal cortex, through the hippocampus, to the isocortex. The neuronal loss is heterogeneous and area-specific. Its mechanism is still discussed. The timing of the synaptic loss, probably linked to Abeta peptide itself, maybe as oligomers, is also controversial. Various clinico-pathological types of Alzheimer disease have been described, according to the type of the lesions (plaque only and tangle predominant), the type of onset (focal onset), the cause (genetic or sporadic) and the associated lesions (Lewy bodies, vascular lesions, hippocampal sclerosis, TDP-43 inclusions and argyrophilic grain disease).

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The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system.

Hwan-Ching Tai, Alberto Serrano-Pozo, Tadafumi Hashimoto … (2012)

In Alzheimer disease (AD), deposition of neurofibrillary tangles and loss of synapses in the neocortex and limbic system each correlate strongly with cognitive impairment. Tangles are composed of misfolded hyperphosphorylated tau proteins; however, the link between tau abnormalities and synaptic dysfunction remains unclear. We examined the location of tau in control and AD cortices using biochemical and morphologic methods. We found that, in addition to its well-described axonal localization, normal tau is present at both presynaptic and postsynaptic terminals in control human brains. In AD, tau becomes hyperphosphorylated and misfolded at both presynaptic and postsynaptic terminals, and this abnormally posttranslationally modified tau is enriched in synaptoneurosomal fractions. Synaptic tau seems to be hyperphosphorylated and ubiquitinated, and forms stable oligomers resistant to SDS denaturation. The accumulation of hyperphosphorylated tau oligomers at human AD synapses is associated with increased ubiquitinated substrates and increased proteasome components, consistent with dysfunction of the ubiquitin-proteasome system. Our findings suggest that synaptic hyperphosphorylated tau oligomers may be an important mediator of the proteotoxicity that disrupts synapses in AD. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation.

Ole Paulsen, Elizabeth Tunbridge, Christine Acton … (2011)

Amyloid β (Aβ) and tau protein are both implicated in memory impairment, mild cognitive impairment (MCI), and early Alzheimer's disease (AD), but whether and how they interact is unknown. Consequently, we asked whether tau protein is required for the robust phenomenon of Aβ-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. We used wild-type mice and mice with a genetic knock-out of tau protein and recorded field potentials in an acute slice preparation. We demonstrate that the absence of tau protein prevents Aβ-induced impairment of LTP. Moreover, we show that Aβ increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Aβ and prevents Aβ-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Aβ to impair synaptic plasticity in the hippocampus and suggest that the Aβ-induced impairment of LTP is mediated by tau phosphorylation. We conclude that preventing the interaction between Aβ and tau could be a promising strategy for treating cognitive impairment in MCI and early AD.

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Journal

Journal ID (nlm-ta): J Neuropathol Exp Neurol

Journal ID (iso-abbrev): J. Neuropathol. Exp. Neurol

Journal ID (publisher-id): NEN

Title: Journal of Neuropathology and Experimental Neurology

Publisher: American Association of Neuropathologists

ISSN (Print): 0022-3069

ISSN (Electronic): 1554-6578

Publication date (Print): December 2014

Publication date (Electronic): 17 November 2014

Volume: 73

Issue: 12

Pages: 1166-1182

Affiliations

From the School of Biology, University of St. Andrews, St. Andrews (EB, FG-M); Centre for Cognitive and Neural Systems and Euan MacDonald Centre, School of Biomedical Sciences, University of Edinburgh, Edinburgh (AH, TS-J); and Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford (DAM), United Kingdom.

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Send correspondence and reprint requests to: Frank Gunn-Moore, PhD, University of St. Andrews, School of Biology, Medical and Biological Sciences Bldg, North Haugh, St. Andrews, Fife, KY16 9TF, UK; E-mail: fjg1@ 123456st-andrews.ac.uk

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Publisher ID: NEN14155 Accession ID: 00009

DOI: 10.1097/NEN.0000000000000138

PMC ID: 4238966

PubMed ID: 25383639

SO-VID: bcd172af-717b-4d6b-921e-ec45b835336c

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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Keywords: alzheimer disease,cortical neurons,efhd2,frontotemporal dementia,frontotemporal lobar degeneration,swiprosin-1,synapses

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Keywords: alzheimer disease, cortical neurons, efhd2, frontotemporal dementia, frontotemporal lobar degeneration, swiprosin-1, synapses

The Calcium-Binding Protein EFhd2 Modulates Synapse Formation In Vitro and Is Linked to Human Dementia

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Most cited references 41

Classification and basic pathology of Alzheimer disease.

The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system.

Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation.

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