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Axon degeneration is key component of neuronal death in amyloid-? toxicity.

ABSTRACT: Depending upon the stimulus, neuronal cell death can either be triggered from the cell body (soma) or the axon. We investigated the origin of the degeneration signal in amyloid ? (A?) induced neuronal cell death in cultured in vitro hippocampal neurons. We discovered that A?1-42 toxicity-induced axon degeneration precedes cell death in hippocampal neurons. Overexpression of Bcl-xl inhibited both axonal and cell body degeneration in the A?-42 treated neurons. Nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) blocks axon degeneration in a variety of paradigms, but it cannot block neuronal cell body death. Therefore, if the neuronal death signals in A?1-42 toxicity originate from degenerating axons, we should be able to block neuronal death by inhibiting axon degeneration. To explore this possibility we over-expressed Nmnat1 in hippocampal neurons. We found that inhibition of axon degeneration in A?1-42 treated neurons prevented neuronal cell death. Thus, we conclude that axon degeneration is the key component of A?1-42 induced neuronal degeneration, and therapies targeting axonal protection can be important in finding a treatment for Alzheimer's disease.

SUBMITTER: Alobuia WM

PROVIDER: S-EPMC3918889 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Axon degeneration is key component of neuronal death in amyloid-β toxicity.

Alobuia Wilson M WM Xia Wei W Vohra Bhupinder P S BP

Neurochemistry international 20130929 8

Depending upon the stimulus, neuronal cell death can either be triggered from the cell body (soma) or the axon. We investigated the origin of the degeneration signal in amyloid β (Aβ) induced neuronal cell death in cultured in vitro hippocampal neurons. We discovered that Aβ1-42 toxicity-induced axon degeneration precedes cell death in hippocampal neurons. Overexpression of Bcl-xl inhibited both axonal and cell body degeneration in the Aβ-42 treated neurons. Nicotinamide mononucleotide adenylylt ...[more]

PMID: 24083988

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Project description:BackgroundThe deposition of the amyloid β-peptide (Aβ) in the brain is one of the hallmarks of Alzheimer's disease (AD). It is not yet clear whether Aβ always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: APP48 and APP23 mice. The APP48 mouse expresses Aβ1-42 with a signal sequence in neurons. These animals produce intracellular Aβ independent of amyloid precursor protein (APP) but do not develop extracellular Aβ plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular Aβ plaques and intracellular Aβ aggregates.ResultsTracing of commissural neurons in layer III of the frontocentral cortex with the DiI tracer revealed no morphological signs of dendritic degeneration in APP48 mice compared to littermate controls. In contrast, the dendritic tree of highly ramified commissural frontocentral neurons was altered in 15-month-old APP23 mice. The density of asymmetric synapses in the frontocentral cortex was reduced in 3- and 15-month-old APP23 but not in 3- and 18-month-old APP48 mice. Frontocentral neurons of 18-month-old APP48 mice showed an increased proportion of altered mitochondria in the soma compared to wild type and APP23 mice. Aβ was often seen in the membrane of neuronal mitochondria in APP48 mice at the ultrastructural level.ConclusionsThese results indicate that APP-independent intracellular Aβ accumulation in APP48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas APP-derived extra- and intracellular Aβ pathology in APP23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, Aβ aggregates in APP23 and APP48 mice induce neurodegeneration presumably by different mechanisms and APP-related production of Aβ may, thereby, play a role for the degeneration of neurites and synapses.

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Axon degeneration is key component of neuronal death in amyloid-? toxicity.

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Axon degeneration is key component of neuronal death in amyloid-β toxicity.

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