Review: Axon pathology in age‐related neurodegenerative disorders

Abstract

'Dying back' axon degeneration is a prominent feature of many age-related neurodegenerative disorders and is widespread in normal ageing. Although the mechanisms of disease- and age-related losses may differ, both contribute to symptoms. Here, we review recent advances in understanding axon pathology in age-related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. In particular, we highlight the importance of axonal transport, autophagy, traumatic brain injury and mitochondrial quality control. We then place these disease mechanisms in the context of changes to axons and dendrites that occur during normal ageing. We discuss what makes ageing such an important risk factor for many neurodegenerative disorders and conclude that the processes of normal ageing and disease combine at the molecular, cellular or systems levels in a range of disorders to produce symptoms. Pathology identical to disease also occurs at the cellular level in most elderly individuals. Thus, normal ageing and age-related disease are inextricably linked and the term 'healthy ageing' downplays the important contributions of cellular pathology. For a full understanding of normal ageing or age-related disease we must study both processes.

ß-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network

“…Thus local Aβ deposits generate fast propagation of degenerative signals across networks leading to early dysfunctions in remote areas. Our results show that local somato-dendritic (but not axonal) Aβ triggers distal-to-proximal axonal degeneration before any somato-dendritic abnormalities, a process reminiscent of dying-back pattern observed in various neurodegenerative syndromes [14]. Thus Aβ toxicity depends not only Figure 2 Axonal administration of NAD+, broad-spectrum caspase inhibitor, and JNK inhibitor reduces Aβ-induced axonal degeneration.…”

Presynaptic Alpha-Synuclein Aggregation in a Mouse Model of Parkinson's Disease

“…These proteinase K-resistant aggregates could be causing immediate presynaptic abnormalities, as evidenced by the lack of synapsin in these synapses, but may also trigger a second slower process of degeneration requiring months to develop, which leads to decreased presynaptic neurotransmitter levels. Ultimately, this chronic synaptic dysfunction may lead to a "dying back" of affected axonal processes, as has been postulated to occur in several synucleinopathies (Adalbert and Coleman, 2012;Yasuda et al, 2013). Alternatively, it is possible that the presynaptic microaggregates we measure may be beneficial because evidence suggests that certain ␣-synuclein aggregate species may be cytoprotective, potentially sequestering other more toxic species such as small oligomers (Nakamura et al, 2011) and therefore reducing neurodegeneration (Tofaris and Spillantini, 2005;Bodner et al, 2006).…”

Recent Progress of the Golgi Technique and Electron Microscopy To Examine Dendritic Pathology In Alzheimer‘s Disease

“…Recent studies have also revealed the molecular mechanisms underlying synapse and spine pathology [8,22,23]. Studies on cell cultures, exposed to oligomers of bamyloid peptide, which combined immune staining and electron microscopy, revealed that a fraction of neurons demonstrate increased tau phosphorylation, redistribution of tau into neuronal soma and dendrites, local elevation of calcium, loss of spines, pronounced depletion of cytoskeleton and a depletion of mitochondria [8,22,23].…”

“…Studies on cell cultures, exposed to oligomers of bamyloid peptide, which combined immune staining and electron microscopy, revealed that a fraction of neurons demonstrate increased tau phosphorylation, redistribution of tau into neuronal soma and dendrites, local elevation of calcium, loss of spines, pronounced depletion of cytoskeleton and a depletion of mitochondria [8,22,23]. It should be emphasized that mitochondrial pathology is particularly obvious in dystrophic dendritic profiles and correlates substantially with the morphological and morphometric alteration of the spines [19].…”