The amyloid precursor protein modulates the position and length of the axon initial segment offering a new perspective on Alzheimer’s disease genetics

Ma, Fulin; Xu, Jianquan; Liu, Yang; Popova, Dina; Youssef, Mark M.; Hart, Ronald P.; Herrup, Karl

doi:10.1101/2022.01.23.477413

Cited by 3 publications

(2 citation statements)

References 75 publications

(78 reference statements)

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“…Cultured neurons express βIII tubulin throughout the cell, but not as strongly in axonal processes ( 34 ). We previously found that processes in human iN cells stained for ankyrin G, identifying the axonal initial segment, which similarly lacked βIII-tubulin ( 35 ). Detection of GIRK2 primarily on βIII-tubulin + /MAP - processes, therefore, suggests pre-axonal, and likely presynaptic, localization.…”

Section: Resultsmentioning

confidence: 99%

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Alcohol reverses the effects ofKCNJ6(GIRK2) noncoding variants on excitability of human glutamatergic neurons

Popova

Gameiro‐Ros

Youssef

et al. 2022

Preprint

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Synonymous and noncoding single nucleotide polymorphisms (SNPs) in the KCNJ6 gene, encoding G protein-gated inwardly rectifying potassium (GIRK2) channel subunit 2, have been linked with increased electroencephalographic frontal theta event-related oscillations (ERO) in subjects diagnosed with alcohol use disorder (AUD). To identify molecular and cellular mechanisms while retaining the appropriate genetic background, we generated induced excitatory glutamatergic neurons (iN) from iPSCs derived from four AUD-diagnosed subjects with KCNJ6 variants (Affected: AF) and four control subjects without variants (Unaffected: UN). Neurons were analyzed for changes in gene expression, morphology, excitability and physiological properties. Single cell RNA sequencing suggests that KCNJ6 AF variant neurons have altered patterns of synaptic transmission and cell projection morphogenesis. Results confirm that AF neurons express lower levels of GIRK2, have greater neurite area, and elevated excitability. Interestingly, exposure to intoxicating concentrations of ethanol induces GIRK2 expression and reverses functional effects in AF neurons. Ectopic overexpression of GIRK2 alone mimics the effect of ethanol to normalize induced excitability. We conclude that KCNJ6 variants decrease GIRK2 expression and increase excitability and that this effect can be minimized or reduced with ethanol.

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Section: Resultsmentioning

confidence: 99%

“…Cultured neurons express βIII tubulin throughout the cell, but not as strongly in axonal processes 57 . We previously found that processes in human iN cells stained for ankyrin G, identifying the axonal initial segment, which similarly lacked βIII-tubulin 58 .…”

Section: Gene Expression Patterns Predict Functional Differences Betw...mentioning

confidence: 94%

Alcohol reverses the effects ofKCNJ6(GIRK2) noncoding variants on excitability of human glutamatergic neurons

Popova

Gameiro‐Ros

Youssef

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons

et al. 2022

Self Cite

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Synonymous and noncoding single nucleotide polymorphisms (SNPs) in the KCNJ6 gene, encoding G protein-gated inwardly rectifying potassium channel subunit 2 (GIRK2), have been linked with increased electroencephalographic frontal theta event-related oscillations (ERO) in subjects diagnosed with alcohol use disorder (AUD). To identify molecular and cellular mechanisms while retaining the appropriate genetic background, we generated induced excitatory glutamatergic neurons (iN) from iPSCs derived from four AUD-diagnosed subjects with KCNJ6 variants (“Affected: AF”) and four control subjects without variants (“Unaffected: UN”). Neurons were analyzed for changes in gene expression, morphology, excitability and physiological properties. Single-cell RNA sequencing suggests that KCNJ6 AF variant neurons have altered patterns of synaptic transmission and cell projection morphogenesis. Results confirm that AF neurons express lower levels of GIRK2, have greater neurite area, and elevated excitability. Interestingly, exposure to intoxicating concentrations of ethanol induces GIRK2 expression and reverses functional effects in AF neurons. Ectopic overexpression of GIRK2 alone mimics the effect of ethanol to normalize induced excitability. We conclude that KCNJ6 variants decrease GIRK2 expression and increase excitability and that this effect can be minimized or reduced with ethanol.

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Cuprizone drives divergent neuropathological changes in different mouse models of Alzheimer’s disease

Cheng

Huang

et al. 2023

Preprint

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Myelin degradation is a normal feature of brain aging that accelerates in Alzheimer's disease (AD). To date, however, the underlying biological basis of this correlation remains elusive. The amyloid cascade hypothesis predicts that demyelination is caused by increased levels of the β-amyloid (Aβ) peptide. Here we report on work supporting the alternative hypothesis that early demyelination is upstream of amyloid. We challenged two different mouse models of AD (R1.40 and APP/PS1) using cuprizone-induced demyelination and tracked the responses with both neuroimaging and neuropathology. In oppose to amyloid cascade hypothesis, R1.40 mice, carrying only a single human mutant APP (Swedish; APPSWE) transgene, showed a more abnormal changes of magnetization transfer ratio and diffusivity than in APP/PS1 mice, which carry both APPSWE and a second PSEN1 transgene (delta exon 9; PSEN1dE9). Although cuprizone targets oligodendrocytes (OL), magnetic resonance spectroscopy and targeted RNA-seq data in R1.40 mice suggested a possible metabolic alternation in axons. In support of alternative hypotheses, cuprizone induced significant intraneuronal amyloid deposition in young APP/PS1, but not in R1.40 mice, and it suggested the presence of PSEN deficiencies, may accelerate Aβ deposition upon demyelination. In APP/PS1, mature OL is highly vulnerable to cuprizone with significant DNA double strand breaks (53BP1+) formation. Despite these major changes in myelin, OLs, and Aβ immunoreactivity, no cognitive impairment or hippocampal pathology was detected in APP/PS1 mice after cuprizone treatment. Together, our data supports the hypothesis that myelin loss can be the cause, but not the consequence, of AD pathology.

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The amyloid precursor protein modulates the position and length of the axon initial segment offering a new perspective on Alzheimer’s disease genetics

Cited by 3 publications

References 75 publications

Alcohol reverses the effects ofKCNJ6(GIRK2) noncoding variants on excitability of human glutamatergic neurons

Alcohol reverses the effects ofKCNJ6(GIRK2) noncoding variants on excitability of human glutamatergic neurons

Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons

Cuprizone drives divergent neuropathological changes in different mouse models of Alzheimer’s disease

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