Amyloid precursor protein (APP) contributes to pathology in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Abstract

In amyotrophic lateral sclerosis (ALS), the progressive loss of motor neurons is accompanied by extensive muscle denervation, resulting in paralysis and ultimately death. Upregulation of amyloid beta (A4) precursor protein (APP) in muscle fibres coincides with symptom onset in both sporadic ALS patients and the SOD1(G93A) mouse model of familial ALS. We have further characterized this response in SOD1(G93A) mice and also revealed elevated levels of β-amyloid (Aβ) peptides in the SOD1(G93A) spinal cord, which were predominantly localized within motor neurons and their surrounding glial cells. We therefore examined the effect of genetic ablation of APP on disease progression in SOD1(G93A) mice, which significantly improved multiple disease parameters, including innervation, motor function, muscle contractile characteristics, motor unit and motor neuron survival. These results therefore strongly suggest that APP actively contributes to SOD1(G93A)-mediated pathology. Together with observations from ALS cases, this study indicates that APP may contribute to human ALS pathology.

Special Issue: Treatment of Genetic Disease

“…This method was applied for identifying the defective APP-mRNA isoform in Lesch-Nyhan disease (LND) (a rare X-linked inherited neurogenetic disorder of purine metabolism affecting 1 in 380,000 people, and caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase, HGprt, EC 2.4.2.8; MIM 308000) [52,53], and in a neurodevelopmental disorder resulting from a nonsense mutation in the Ox-2 antigen domain of APP gene [54]: APP-mRNA isoform of 624 bp, with a deletion starting after 49 bp of the 5' end of exon 3 followed by a complete deletion of exons 4-15, mutations in exon 1: c.22C>T, p.L8F, and exon 3: c.269A>G, p.Q90R encoding APP 207 isoform, was found [52,54]. This method will be useful for identifying the defective APP-mRNA isoform in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism [55], fragile X syndrome [56], amyotrophic lateral sclerosis [57], multiple sclerosis [58], and AD [56,59]. Once the defective APP-mRNA isoform responsible for the disease is identified, one of the potential treatment for the disease may include the inhibition or repression of translation into the damaged APP protein isoform from the defective APP-mRNA isoform by using antisense drugs [60].…”

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“…In ALS model mice, APP and Aβ are both upregulated in spinal cord [74] and overexpression of Aβ has been shown to accelerate the onset of motor impairment [79]. Furthermore, the studies of Herman et al, [80] revealed that increasing Aβ42 increased the Tar-DNA binding Protein (TDP43) inclusions found in the majority of ALS patients.…”

“…Therefore, compounds directed to modifying APP-related effects in AD may exert therapeutic effects in ALS as well. Since both Aβ increases and sAPPα decreases have recently been associated with ALS [74,75], we hypothesize that sAPPα enhancers such as F03 may be of benefit either as monotherapy or in combination therapy.…”

“…Therefore, compounds directed to modifying APP-related effects in AD may exert therapeutic effects in ALS as well. Since both Aβ increases and sAPPα decreases have recently been associated with ALS [74,75], we hypothesize that sAPPα enhancers such as F03 may be of benefit either as monotherapy or in combination therapy.In Yoon et al, [76] it was revealed that Aβ interacts with Super Oxide Dismutase 1 (SOD1) resulting in a reduction in SOD activity, an increase in oxidative stress, and the compromised mitochondrial function that is characteristic of ALS [77,78]. In ALS model mice, APP and Aβ are both upregulated in spinal cord [74] and overexpression of Aβ has been shown to accelerate the onset of motor impairment [79].…”

Epigenetics in Rare Diseases

“…APP, a house keeping gene [30] and endogenous ligand (http:// www.genenames.org/genefamilies/ENDOLIG), is an important molecular hub at the center of interacting pathways and acts as a permissive factor for various neurodevelopmental and neural circuit processes [31], altered APP processing may affect brain function through a host of altered cellular and molecular events. My findings may provide new directions not only for investigating the role of APP in neuropathology associated with LND but also for the research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism [32], fragile X syndrome [33], amyotrophic lateral sclerosis [34], and AD [33,35], and may pave the way for new strategies applicable to rational antisense drugs design [36].…”