Motor Deficit in a Tauopathy Model Is Induced by Disturbances of Axonal Transport Leading to Dying-Back Degeneration and Denervation of Neuromuscular Junctions

Abstract

Several neurodegenerative diseases are characterized by both cognitive and motor deficits associated with accumulation of tau aggregates in brain, brainstem, and spinal cord. The Tg30 murine tauopathy model expresses a human tau protein bearing two frontotemporal dementia with Parkinsonism linked to chromosome 17 pathogenic mutations and develops a severe motor deficit and tau aggregates in brain and spinal cord. To investigate the origin of this motor deficit, we analyzed the age-dependent innervation status of the neuromuscular junctions and mutant tau expression in Tg30 mice. The human transgenic tau was detected from postnatal day 7 onward in motoneurons, axons in the sciatic nerve, and axon terminals of the neuromuscular junctions. The development and maturation of neuromuscular junctions were not disrupted in Tg30 mice, but their maintenance was disturbed in adult Tg30 mice, resulting in a progressive and severe muscle denervation. This muscle denervation was associated with early electrophysiological signs of muscle spontaneous activities and histological signs of muscle degeneration. Early loss of synaptic vesicles in axon terminals preceding motor deficits, accumulation of Gallyas-positive aggregates, and cathepsin-positive vesicular clusters in axons in the sciatic nerve suggest that this denervation results from disturbances of axonal transport. This physiopathological mechanism might be responsible for motor signs observed in some human tauopathies, and for synaptic dysfunction resulting from alterations at the presynaptic level in these diseases. (Am J Pathol 2015 http://dx

Mitochondrial Mechanisms of Neuromuscular Junction Degeneration with Aging

“…This is consistent with other observations in aging muscle suggesting a motoneuron die-back phenomenon [56]. Interestingly, this 'dying-back' phenomenon is a common feature in several neurodegenerative conditions affecting muscle [57][58][59], and in these settings mitochondria in the motoneuron terminals are frequently affected [59,60], supporting the notion that mitochondrial-mediated axonal die-back is likely relevant to aging muscle atrophy. A key question, however, is what factors are responsible for accumulation of dysfunctional mitochondria in the terminals.…”

Age Related Changes in Muscle Mass and Force Generation in the Triple Transgenic (3xTgAD) Mouse Model of Alzheimer’s Disease

“…Consistent with this idea, Aβ accumulation in muscle tissue is associated with muscle atrophy in inclusion body myopathy ( Fukuchi et al, 1998 ) and in a recent study in a mouse model with Aβ accumulation (Tg2576 mice), Torcinaro et al (2021) reported reduced cholinergic innervation of skeletal muscle that potentially contributes to sarcopenia. Tau overexpressing mice (Tg30 mice) also show motor dysfunction in mice at 8 months of age, including axonopathy, muscle atrophy, and decreased NMJ innervation ( Audouard et al, 2015 ). Interestingly, we observed a significant decrease in muscle mass, but not strength, in old 3xTgAD mice compared to age-matched control mice.…”

Microtubules in health and degenerative disease of the nervous system

“…Relevant to Alzheimer's disease, beta amyloid has been shown to impair hippocampal long-term potentiation and promote dendritic spine loss through a pathway involving kinesin-5 (100), a motor protein that may contribute to the regulation of microtubule polarity orientation in dendrites (72). Audouard et al (101) recently showed that disrupted axonal transport precedes progressive muscle denervation in mice expressing pathogenic human tau, while Stevenson et al (102) used squid giant axon to show that amyloid precursor protein interacts at the organelle/microtubule interface, possibly mediating vesicular transport and Alzheimer's pathology. Gan et al (103) proposed that the disruption of axonal transport by a mutant kinesin light chain-1 splice variant in Alzheimer's disease follows a progression of reduced axonal transport, which leads to accumulation of protein aggregates, followed by an ER stress response.…”