In model mice that overexpress mutant human APP, synaptic dysfunction, spine morphology alteration, and axonal transport defects were observed in association with intracellular Aβ oligomers (iAβOs). Īlthough a role for eAβOs in causing AD-like toxicity is well established, several studies have revealed that intraneuronal accumulation of Aβ is also toxic and precedes its extracellular deposition in patients and model mice of AD. Thus, impaired transport of mitochondria and BDNF might contribute to synaptic dysfunction in AD. Once secreted from axon terminals, BDNF increases spine density and the proportion of mature spines by interacting with postsynaptic TrkB receptors at the target cell membrane. Mitochondria are needed at presynaptic boutons to maintain neurotransmission by producing ATP and buffering synaptic calcium (Ca 2+). In axons, eAβOs impair transport of cargoes such as mitochondria and vesicles containing brain-derived neurotrophic factor (BDNF), which are both required for neuronal form and function. eAβO binding also alters spine morphology and decreases spine density. At the postsynaptic membrane, eAβOs interact with glutamate receptors and dysregulate calcium influx to impair long-term potentiation (LTP) and enhance long-term depression (LTD). According to one central view of AD pathogenesis, extracellular Aβ oligomers (eAβOs) bind plasma membrane targets to elicit pre- and postsynaptic intracellular effects (for reviews, ). Soluble oligomers of amyloid β (Aβ), which are generated from the amyloid precursor protein (APP), are believed to be the primary synaptotoxins in AD. Synaptic dysfunction is an early event in Alzheimer’s disease (AD). Our findings indicate that intracellular Aβ oligomers likely contribute to early synaptic pathology in AD and argue against the consensus that Aβ-induced spine loss and transport defects require tau. A reduction in BDNF transport by intracellular Aβ oligomers was also observed in tau knockout neurons. We also found that intracellular Aβ oligomers significantly impaired the intracellular transport of BDNF, mitochondria, and recycling endosomes: cargoes essential for synaptic maintenance. We found that intracellular Aβ oligomers caused a reduction in mushroom, or mature spines, independently of tau. First we investigated the effects of intracellular Aβ oligomers on dendritic spines in primary neurons and their tau-dependency using tau knockout neurons. We compared the effects of wild-type and Osaka (E693Δ)-mutant amyloid precursor proteins: the former secretes Aβ into extracellular space and the latter accumulates Aβ oligomers within cells. However, the links between intracellular Aβ, spine alteration, and mechanisms that support synaptic maintenance such as organelle trafficking are poorly understood. Meanwhile, intraneuronal accumulation of Aβ precedes its extracellular deposition and is also associated with synaptic dysfunction in AD. Extracellular amyloid β (Aβ) oligomers cause spine alterations and impede the transport of proteins and organelles such as brain-derived neurotrophic factor (BDNF) and mitochondria that are required for synaptic function. Synaptic dysfunction and intracellular transport defects are early events in Alzheimer’s disease (AD).
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