Effects and mechanisms of APP and its cleavage product Aβ in the comorbidity of sarcopenia and Alzheimer's disease

Abstract

Sarcopenia and AD are both classic degenerative diseases, and there is growing epidemiological evidence of their comorbidity with aging; however, the mechanisms underlying the biology of their commonality have not yet been thoroughly investigated. APP is a membrane protein that is expressed in tissues and is expressed not only in the nervous system but also in the NMJ and muscle. Deposition of its proteolytic cleavage product, Aβ, has been described as a central component of AD pathogenesis. Recent studies have shown that excessive accumulation and aberrant expression of APP in muscle lead to pathological muscle lesions, but the pathogenic mechanism by which APP and its proteolytic cleavage products act in skeletal muscle is less well understood. By summarizing and analyzing the literature concerning the role, pathogenicity and pathological mechanisms of APP and its cleavage products in the nervous system and muscles, we aimed to explore the intrinsic pathological mechanisms of myocerebral comorbidities and to provide new perspectives and theoretical foundations for the prevention and treatment of AD and sarcopenia comorbidities.

Keywords: AD; amyloid precursor protein; cleavage products; intervention; myocerebral comorbidity; sarcopenia.

Figure 1

The structural pattern diagram of APP. APP can be divided into three regions, AICD, E2 and E1, and each region performs different functions. Created with BioRender.com.

Figure 2

Schematic diagram of the hydrolysis path of APP. (A) The nonamyloid protein pathway, which is cleaved sequentially by α secretase and γ secretase to obtain AICD, P3 and sAPPα. (B) The amyloid protein pathway, which is cleaved sequentially by β-secretase and γ-secretase to obtain AICD, Aβ and sAPPβ. (C) The third pathway of APP hydrolysis, which involves cleavage by η, α, β and γ secretases in turn to obtain AICD, P3, Aβ, Aη-α, Aη-β and sAPP-η. Created with BioRender.com.

Figure 3

Main effects of Aβ on neurons, microglia, and astrocytes in the brain. The left panel represents a healthy brain with small amounts of Aβ. The right panel shows that large amounts of Aβ induce adverse reactions such as autophagic dysfunction, inflammation, oxidative stress, calcium imbalance, and impaired synaptic function. This affects the function of neurons and glial cells, ultimately causing harm to the brain. Created with BioRender.com.

Figure 4

Effect of Aβ on the NMJ formation process. (A) APP interacts with LRP4 and agrin to regulate NMJ formation. APP interacts with LRP4 and activates Musk. The synergistic binding of APP and agrin to LRP4 further strengthens the interaction between LRP4 and APP in muscle, promoting synaptic differentiation and the maintenance of postnatal NMJs. (B) APP hydrolysis leads to the failure of LRP4 binding to APP and the collapse of its domain, which fails to activate Musk and reduces AChR aggregation on the sarcolemma, leading to muscle fiber denervation. Moreover, it affects the development of the NMJ, and the degeneration of the NMJ leads to a reduction in CHT targeting. In addition, the activation of classical inflammation, oxidative stress and calcium ion imbalance by Aβ may also be a potential signaling pathway, but more experimental evidence is needed to confirm these findings. Created with BioRender.com.

Figure 5

Aβ deposition in Skeletal Muscle in Sarcopenia. (A) Healthy skeletal muscle, where satellite cells retain their differentiation capabilities, and the mitochondria, endoplasmic reticulum, and sarcoplasmic reticulum function normally. (B) Process of single-stranded Aβ aggregating into oAβ. (C) The series of physiological and biochemical reactions resulting from Aβ deposition in muscle. These reactions impair the normal function of cellular organelles, leading to muscle cell damage and the inhibition of satellite cell proliferation and differentiation. Created with BioRender.com.

Figure 6

Effect of exercise intervention on Aβ in the brain, NMJ, and muscle in patients with myocerebral comorbidities. The left side shows the brain, NMJ, and muscle of patients with myocerebral comorbidities. After the deposition of Aβ was reduced through exercise, the shape and size of the brain and muscle of the patients changed significantly and gradually changed in the direction of the healthy people on the right side. Previous studies have shown that exercise can improve the integrity of the NMJ in patients. However, whether reducing Aβ through exercise can lead to improvements in NMJ integrity and the underlying mechanisms need to be further studied. Created with BioRender.com.