Loss of all three APP family members during development impairs synaptic function and plasticity, disrupts learning, and causes an autism‐like phenotype

Steubler, Vicky; Erdinger, Susanne; Back, Michaela Kerstin; Ludewig, Susann; Fässler, Dominique; Richter, M.; Han, Kang; Slomianka, Lutz; Amrein, Irmgard; Engelhardt, Jakob von; Wolfer, David P; Körte, Martin; Müller, Ulrike

doi:10.15252/embj.2020107471

Cited by 31 publications

(46 citation statements)

References 89 publications

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“…Previous studies showed that the perturbation of APP (and/or APLPs) induces severe cognitive deficits in mice ( 42 , 43 ). Specifically, forebrain GABAergic neuron-specific APP/APLP2 double-cKO mice exhibit impaired hippocampus-dependent spatial learning and memory ( 42 ).…”

Section: Resultsmentioning

confidence: 99%

MDGA1 negatively regulates amyloid precursor protein–mediated synapse inhibition in the hippocampus

Kim

et al. 2022

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

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Balanced synaptic inhibition, controlled by multiple synaptic adhesion proteins, is critical for proper brain function. MDGA1 (meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu [MAM] domain-containing glycosylphosphatidylinositol anchor protein 1) suppresses synaptic inhibition in mammalian neurons, yet the molecular mechanisms underlying MDGA1-mediated negative regulation of GABAergic synapses remain unresolved. Here, we show that the MDGA1 MAM domain directly interacts with the extension domain of amyloid precursor protein (APP). Strikingly, MDGA1-mediated synaptic disinhibition requires the MDGA1 MAM domain and is prominent at distal dendrites of hippocampal CA1 pyramidal neurons. Down-regulation of APP in presynaptic GABAergic interneurons specifically suppressed GABAergic, but not glutamatergic, synaptic transmission strength and inputs onto both the somatic and dendritic compartments of hippocampal CA1 pyramidal neurons. Moreover, APP deletion manifested differential effects in somatostatin- and parvalbumin-positive interneurons in the hippocampal CA1, resulting in distinct alterations in inhibitory synapse numbers, transmission, and excitability. The infusion of MDGA1 MAM protein mimicked postsynaptic MDGA1 gain-of-function phenotypes that involve the presence of presynaptic APP. The overexpression of MDGA1 wild type or MAM, but not MAM-deleted MDGA1, in the hippocampal CA1 impaired novel object-recognition memory in mice. Thus, our results establish unique roles of APP–MDGA1 complexes in hippocampal neural circuits, providing unprecedented insight into trans-synaptic mechanisms underlying differential tuning of neuronal compartment-specific synaptic inhibition.

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Section: Resultsmentioning

confidence: 99%

MDGA1 negatively regulates amyloid precursor protein–mediated synapse inhibition in the hippocampus

Kim

et al. 2022

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

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“…This may result from the functional redundancy of APP and APP-like proteins (APLP1 and ALPL2). In accordance, constitutive triple knockout mice (TKO) die after birth (Heber et al, 2000), whereas Nex-Cre cTKO (conditional triple KO in excitatory forebrain neurons starting during embryonic development) present gross brain morphology alterations (Steubler et al, 2021), showing a crucial role for APP family members during development. Our combination of in vitro silencing and acute interference of the APP C-terminal domain ex vivo , overcome a possible compensation by APP family members, while allowing to study APP specifically during postnatal developmental stages.…”

Section: Discussionmentioning

confidence: 99%

Age-dependent NMDA receptor function is regulated by the Amyloid Precursor Protein

Rajão‐Saraiva

Temido‐Ferreira

Coelho

et al. 2022

Preprint

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N-methyl-D-aspartate receptors (NMDARs) are critical for the maturation and plasticity of glutamatergic synapses. In the hippocampus, NMDARs mainly contain GluN2A and/or GluN2B regulatory subunits. The amyloid precursor protein (APP) has emerged as a putative regulator of NMDARs, but the impact of this interaction to their function is largely unknown. By combining patch-clamp electrophysiology and molecular approaches, we unravel a dual mechanism by which APP controls GluN2B-NMDARs, depending on the life stage. We show that APP is highly abundant specifically at the postnatal postsynapse. It interacts with GluN2B-NMDARs, controlling its synaptic content and mediated currents, both in infant mice and primary neuronal cultures. Upon aging, the APP amyloidogenic derived C-terminal fragments, rather than APP full length, contribute to aberrant GluN2B-NMDAR currents. Accordingly, we found that the APP processing is increased upon aging, both in mice and human brain, and interfering with this mechanism normalized the aberrant currents. While the first mechanism might be essential for synaptic maturation during development, the latter could contribute to age-related synaptic impairments.

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“…AICD-proteolytic products were shown to translocate to the nucleus where they can activate transcription factors and thus alter the synaptic function [83][84][85][86]. Indeed, APP itself, as well as its homologues and cleavage products, affect dendritic spine numbers [76,[87][88][89][90].…”

Section: Discussionmentioning

confidence: 99%

Amyloid Beta-Mediated Changes in Synaptic Function and Spine Number of Neocortical Neurons Depend on NMDA Receptors

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Ruggieri

Jacobi

et al. 2021

IJMS

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Onset and progression of Alzheimer’s disease (AD) pathophysiology differs between brain regions. The neocortex, for example, is a brain region that is affected very early during AD. NMDA receptors (NMDARs) are involved in mediating amyloid beta (Aβ) toxicity. NMDAR expression, on the other hand, can be affected by Aβ. We tested whether the high vulnerability of neocortical neurons for Aβ-toxicity may result from specific NMDAR expression profiles or from a particular regulation of NMDAR expression by Aβ. Electrophysiological analyses suggested that pyramidal cells of 6-months-old wildtype mice express mostly GluN1/GluN2A NMDARs. While synaptic NMDAR-mediated currents are unaltered in 5xFAD mice, extrasynaptic NMDARs seem to contain GluN1/GluN2A and GluN1/GluN2A/GluN2B. We used conditional GluN1 and GluN2B knockout mice to investigate whether NMDARs contribute to Aβ-toxicity. Spine number was decreased in pyramidal cells of 5xFAD mice and increased in neurons with 3-week virus-mediated Aβ-overexpression. NMDARs were required for both Aβ-mediated changes in spine number and functional synapses. Thus, our study gives novel insights into the Aβ-mediated regulation of NMDAR expression and the role of NMDARs in Aβ pathophysiology in the somatosensory cortex.

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Loss of all three APP family members during development impairs synaptic function and plasticity, disrupts learning, and causes an autism‐like phenotype

Cited by 31 publications

References 89 publications

MDGA1 negatively regulates amyloid precursor protein–mediated synapse inhibition in the hippocampus

MDGA1 negatively regulates amyloid precursor protein–mediated synapse inhibition in the hippocampus

Age-dependent NMDA receptor function is regulated by the Amyloid Precursor Protein

Amyloid Beta-Mediated Changes in Synaptic Function and Spine Number of Neocortical Neurons Depend on NMDA Receptors

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