Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Abstract

The pathological mechanism by which A␤ causes neuronal dysfunction and death remains largely unknown. Deficiencies in fast axonal transport (FAT) were suggested to play a crucial role in neuronal dysfunction and loss for a diverse set of dying back neuropathologies including Alzheimer's disease (AD), but the molecular basis for pathological changes in FAT were undetermined. Recent findings indicate that soluble intracellular oligomeric A␤ (oA␤) species may play a critical role in AD pathology. Real-time analysis of vesicle mobility in isolated axoplasms perfused with oA␤ showed bidirectional axonal transport inhibition as a consequence of endogenous casein kinase 2 (CK2) activation. Conversely, neither unaggregated amyloid beta nor fibrillar amyloid beta affected FAT. Inhibition of FAT by oA␤ was prevented by two specific pharmacological inhibitors of CK2, as well as by competition with a CK2 substrate peptide. Furthermore, perfusion of axoplasms with active CK2 mimics the inhibitory effects of oA␤ on FAT. Both oA␤ and CK2 treatment of axoplasm led to increased phosphorylation of kinesin-1 light chains and subsequent release of kinesin from its cargoes. Therefore pharmacological modulation of CK2 activity may represent a promising target for therapeutic intervention in AD.Alzheimer's disease ͉ Axonal transport ͉ Beta amyloid oligomer ͉ CK2 ͉ Kinesin T he complex functional changes and histopathology of Alzheimer disease (AD) make it one of the most challenging disorders faced by modern medicine. Histopathological hallmarks of AD include distinctive extracellular and intracellular aggregates of amyloid beta (A␤) and tau (1, 2). Synaptic dysfunction and axonopathy appear to be the earliest lesions in AD as corroborated by reduced immunoreactivity of synaptophysin and other synaptic markers in terminal fields of brain-affected areas (3). AD-affected neurons appear to die eventually as a consequence of synaptic dysfunction and loss, following a typical dying-back pattern of neuronal degeneration.The amyloid hypothesis (4), a dominant concept in AD research for many years, has been revised in recent years to include the notion that smaller soluble A␤ aggregates may play an early and significant role in AD. Soluble oligomers of A␤ (oA␤) have been shown to be neurotoxic both in vivo and in vitro (5-7) as well as altering synaptic structure and function (8). Moreover, oA␤ levels correlate with impairments in cognitive function, learning, and memory (9, 10), but the molecular basis of these effects are uncertain. Intracellular A␤ was first described by Wertkin et al. (11). Immunogold electron microscopy showed that intraneuronal A␤ is pre-and postsynaptically enriched in both AD human brain and AD transgenic animal models in association with dystrophic neurites and abnormal synaptic morphology (12)(13)(14). Spatial and temporal analyses of intraneuronal oA␤ accumulation show that it precedes plaque formation in both AD animal models and Down's syndrome patients, suggesting that oA␤ is an early intracellular toxic agent i...

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

“…The progressive tubulin beading after oA␤ transfer shown here could be a sign of axonal disruption (Shah et al, 2009), indicating that oA␤ can cause axonal damage. Other researchers have proposed that axonal damage is part of the process that leads to neurodegeneration in AD (Pigino et al, 2009), and in concordance with this, a gradually increasing disruption of endosomes, a sign of cytotoxicity (Song et al, 2011), was also observed. This observation not only reinforces the role of intracellular A␤ in AD pathogenesis but also establishes the disease relevance associated with the cell-to-cell transfer of intracellular oA␤ .…”

Neuronal and Axonal Loss Are Selectively Linked to Fibrillar Amyloid-β within Plaques of the Aged Primate Cerebral Cortex

“…Because of their soluble characteristics and their ability to move freely within the neuropil, small oligomers and protofibrils can interfere with normal neuronal membrane function and have been demonstrated to hamper synaptic function 22,23 and to inhibit fast axonal transport. 24 They are also associated with memory deficits in animal models of AD. 48 These findings have led to the conclusion that soluble A␤ species may make a significant contribution to the earliest manifestations of cognitive deficits and dementia in man.…”

“…21 Injections of plaque equivalent concentrations (200 pg) of fA␤ into the cerebral cortex of aged rhesus or mormoset monkeys produced significant neuronal loss and induced hyperphosphorylation of tau, both features of the AD brain. Recent in vitro evidence indicates that oA␤, which are believed to form before deposition of A␤ in plaques and are likely to interfere with synaptic function 22,23 and inhibit fast axonal transport, 24 may also lead to neuronal degeneration. [25][26][27][28] However, although there is abundant evidence demonstrating that oligomeric A␤ interferes with neuronal function, direct in vivo demonstration that this conformation of A␤ causes neuronal death is lacking.…”

Cytoplasmic dynein: a key player in neurodegenerative and neurodevelopmental diseases

“…Aβ peptide has been shown to disrupt axonal transport in vitro [44]. Axonal transport is also compromised in aged brains [44]. Several lines of evidence investigating the link between axonal transport machinery and amyloid plaques suggested an involvement of anterograde transport rather than retrograde transport [45].…”

“…APP is the precursor of Aβ peptide and is transported by fast axonal anterograde transport [43]. Aβ peptide has been shown to disrupt axonal transport in vitro [44]. Axonal transport is also compromised in aged brains [44].…”