Our findings may promote development of effective therapeutic compounds for AD prevention and treatment. These results advance our understanding of early AD synaptic pathology because iAβO accumulation precedes extracellular amyloid deposition in patients and AD model mice. Notably, spine reduction and impairment of BDNF transport occurs independently of tau. We found that iAβOs reduced the number of mature spines and impaired transport of BDNF, mitochondria, and recycling endosomes in hippocampal neurons expressing APP OSK. Here, we determined and compared the effects of wild-type APP (APP WT) and Osaka-mutant APP (APP OSK) on dendritic spine morphology and intracellular transport of organelles required for synaptic maintenance and function. Intracellularly, the Osaka mutation-induced iAβOs lead to endoplasmic reticulum stress and damage of mitochondria and organelles within the endosomal/lysosomal system. The Osaka (E693Δ) mutation in APP induces iAβO accumulation without detection of Aβ fibrillization in vitro and without detectable Aβ plaque formation in AD patients or mouse models. Furthermore, although it is widely reported that tau is required for eAβO toxicity (for a review, ), whether iAβO toxicity is tau-dependent has not yet been investigated.Ī valuable model for studying iAβOs is an APP mutation identified in familial AD. Cellular mechanisms that underlie iAβO-induced synaptic dysfunction remain uncharacterized. These pathological changes, however, may have been induced by overexpression of human APP or undetected extracellular Aβ. 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).

Bdnf transport from axon to dendrite