Abstract
Motor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the End-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2−/− mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP family as a potential target for further investigation into the cause and regulation of MND.
Highlights
Motor neurone disease (MND) is a fatal human neurodegenerative disorder, and the most common form of MND is amyotrophic lateral sclerosis (ALS) [1]
amyloid precursorlike protein 2 (APLP2) and amyloid precursor protein (APP) protein expression are upregulated in the human MND spinal cord in a sex‐dependent manner
The APP protein level was significantly upregulated in both sexes too in the SOD1G37R mouse compared to respective WT littermate controls and it was significantly higher in the male compared to the female SOD1-G37R mouse (p < 0.05, Fig. 2B). These results demonstrate that APP and APLP2 protein expression levels are significantly upregulated in the spinal cord at Endstage in SOD1-G37R mouse, an effect that is sex dependent
Summary
Motor neurone disease (MND) is a fatal human neurodegenerative disorder, and the most common form of MND is amyotrophic lateral sclerosis (ALS) [1]. Severity and rate of disease progression [4, 5] whilst age, sex, and various molecular targets are contributing factors [6, 7]. Clinical presentation and severity of the MND with men affected at 1.5-fold higher rate compared to women [5, 10]. This sex difference diminishes at post-menopausal ages [11] suggesting a protective role by estrogens in MND pathophysiology [7]. The occurrence of sex differences in MND subjects makes sex comparison an important variable to be investigated in basic and preclinical research
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