The Amyloid Precursor Protein Modulates the Position and Length of the Axon Initial Segment.
- Authors
- Ma, Fulin; Akolkar, Himanshu; Xu, Jianquan; Liu, Yang; Popova, Dina; Xie, Jiaan; Youssef, Mark M; Benosman, Ryad; Hart, Ronald P; Herrup, Karl
- Year
- 2023
- Journal
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- PMID
- 36717226
- DOI
- 10.1523/JNEUROSCI.0172-22.2023
- PMCID
- PMC10010458
The amyloid precursor protein (APP) is linked to the genetics and pathogenesis of Alzheimer's disease (AD). It is the parent protein of the β-amyloid (Aβ) peptide, the main constituent of the amyloid plaques found in an AD brain. The pathways from APP to Aβ are intensively studied, yet the normal functions of APP itself have generated less interest. We report here that glutamate stimulation of neuronal activity leads to a rapid increase in gene expression. In mouse and human neurons, elevated APP protein changes the structure of the axon initial segment (AIS) where action potentials are initiated. The AIS is shortened in length and shifts away from the cell body. The GCaMP8f Ca reporter confirms the predicted decrease in neuronal activity. NMDA antagonists or knockdown of block the glutamate effects. The actions of APP on the AIS are cell-autonomous; exogenous Aβ, either fibrillar or oligomeric, has no effect. In culture, APP (a familial AD mutation) induces larger AIS changes than wild type APP. Ankyrin G and βIV-spectrin, scaffolding proteins of the AIS, both physically associate with APP, more so in AD brains. Finally, in humans with sporadic AD or in the R1.40 AD mouse model, both females and males, neurons have elevated levels of APP protein that invade the AIS. as , this increased APP is associated with a significant shortening of the AIS. The findings outline a new role for the APP and encourage a reconsideration of its relationship to AD. While the amyloid precursor protein (APP) has long been associated with Alzheimer's disease (AD), the normal functions of the full-length Type I membrane protein have been largely unexplored. We report here that the levels of APP protein increase with neuronal activity. and , modest amounts of excess APP alter the properties of the axon initial segment. The β-amyloid peptide derived from APP is without effect. Consistent with the observed changes in the axon initial segment which would be expected to decrease action potential firing, we show that APP expression depresses neuronal activity. In mouse AD models and human sporadic AD, APP physically associates with the scaffolding proteins of the axon initial segment, suggesting a relationship with AD dementia.
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Axon initial segment dynamics during associative fear learning. | Benoit CM et al. | — | 2026 | → |
| The role of 2-Oxoglutarate dehydrogenase complex mitochondrial enzyme in alzheimer's disease: a literature review and bioinformatics workflow. | Sayehmiri F et al. | — | 2026 | → |
| Axon initial segment structure and function in health and disease. | Jenkins PM et al. | — | 2025 | → |
| Endoplasmic Reticulum Stress Mediates Axon Initial Segment Shortening: Implications for Diabetic Brain Complications. | Shelby JN et al. | — | 2025 | → |
| The dynamic axon initial segment: From neuronal polarity to network homeostasis. | Fréal A et al. | — | 2025 | → |
| The Primary Cilia are Associated with the Axon Initial Segment in Neurons. | Wang H et al. | — | 2025 | → |
| Alterations in the axon initial segment plasticity is involved in early pathogenesis in Alzheimer's disease. | Li Y et al. | — | 2024 | → |
| DNA Damage and Senescence in the Aging and Alzheimer's Disease Cortex Are Not Uniformly Distributed. | Gutta G et al. | — | 2024 | → |
| From Organotypic Mouse Brain Slices to Human Alzheimer's Plasma Biomarkers: A Focus on Nerve Fiber Outgrowth. | Yilmaz SN et al. | — | 2024 | → |
| Modifying Alzheimer's disease pathophysiology with photobiomodulation: model, evidence, and future with EEG-guided intervention. | Lim L | — | 2024 | → |
| The amyloid-β peptide: Guilty as charged? | Murphy MP et al. | — | 2024 | → |
| Transcriptomic alterations in APP/PS1 mice astrocytes lead to early postnatal axon initial segment structural changes. | Benitez MJ et al. | — | 2024 | → |
| Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons. | Popova D et al. | — | 2023 | → |
| Alzheimer's disease: an axonal injury disease? | Dan L et al. | — | 2023 | → |
| Amyloid Precursor Protein Can Cause Changes in Neuronal Firing Rates via Axon Initial Segment. | Acharyya D et al. | — | 2023 | → |
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| ApoER2-Dab1 disruption as the origin of pTau-related neurodegeneration in sporadic Alzheimer's disease | Ramsden CE et al. | — | 2023 | — |
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