Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (2): 790-799.doi: 10.4103/NRR.NRR-D-24-01440

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Pathological axonal enlargement in connection with amyloidosis, lysosome destabilization, and bleeding is a major defect in Alzheimer’s disease

Hualin Fu1, 2, 3, *, Jilong Li1 , Chunlei Zhang1, 3, Guo Gao1, 3, Qiqi Ge2, 4, Xinping Guan4, 5, Daxiang Cui1, 3   

  1. 1 Institute of Nano Biomedicine and Engineering, School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China;  2 Institute of Marine Equipment, Shanghai Jiao Tong University, Shanghai, China;  3 National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai, China;  4 Department of Automation, Shanghai Jiao Tong University, Shanghai, China;  5 The Key Laboratory of System Control and Information Processing, Ministry of Education, Shanghai, China
  • Online:2026-02-15 Published:2025-05-24
  • Contact: Hualin Fu, PhD, hfu@sjtu.edu.cn or 1010720220@qq.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81472235 (to HF); the Shanghai Jiao Tong University Medical and Engineering Project, Nos. YG2021QN53 (to HF), YG2017MS71 (to HF); the International Cooperation Project of the National Natural Science Foundation of China, No. 82020108017 (to DC); and the Innovation Group Project of the National Natural Science Foundation of China, No. 81921002 (to DC)

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Abstract: Alzheimer’s disease is a multi-amyloidosis disease characterized by amyloid-β deposits in brain blood vessels, microaneurysms, and senile plaques. How amyloid-β deposition affects axon pathology has not been examined extensively. We used immunohistochemistry and immunofluorescence staining to analyze the forebrain tissue slices of Alzheimer’s disease patients. Widespread axonal amyloidosis with distinctive axonal enlargement was observed in patients with Alzheimer’s disease. On average, amyloid-β-positive axon diameters in Alzheimer’s disease brains were 1.72 times those of control brain axons. Furthermore, axonal amyloidosis was associated with microtubule-associated protein 2 reduction, tau phosphorylation, lysosome destabilization, and several blood-related markers, such as apolipoprotein E, alpha-hemoglobin, glycosylated hemoglobin type A1C, and hemin. Lysosome destabilization in Alzheimer’s disease was also clearly identified in the neuronal soma, where it was associated with the co-expression of amyloid-β, Cathepsin D, alpha-hemoglobin, actin alpha 2, and collagen type IV. This suggests that exogenous hemorrhagic protein intake influences neural lysosome stability. Additionally, the data showed that amyloid-β-containing lysosomes were 2.23 times larger than control lysosomes. Furthermore, under rare conditions, axonal breakages were observed, which likely resulted in Wallerian degeneration. In summary, axonal enlargement associated with amyloidosis, micro-bleeding, and lysosome destabilization is a major defect in patients with Alzheimer’s disease. This finding suggests that, in addition to the well-documented neural soma and synaptic damage, axonal damage is a key component of neuronal defects in Alzheimer’s disease.

Key words: Alzheimer’s disease, amyloid-β, amyloidosis, axonal enlargement, hemoglobin, hemorrhage, lysosome destabilization, neuropil thread, tau, Wallerian degeneration