The biochemical nature of senile plaques: intracellular destabilized-lysosome-enriched neural processes catabolizing extracellular hemorrhagic amyloid materials

Fu, H.; Li, J.; Zhang, C.; Gao, G.; Ge, Q.; Cui, D.

doi:10.64898/2025.12.30.696965

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bioRxiv · 10.64898/2025.12.30.696965

The biochemical nature of senile plaques: intracellular destabilized-lysosome-enriched neural processes catabolizing extracellular hemorrhagic amyloid materials

Fu, H.·Li, J.·Zhang, C.·Gao, G.·Ge, Q.·Cui, D.

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Abstract

The pathological mechanism of senile plaque formation in Alzheimers disease remains a challenging unresolved problem for over one hundred years. In this study, we investigated senile plaque pathogenesis based on immunohistochemistry, fluorescence imaging and quantitative analysis of AD front brain sections with multiple senile plaque related markers such as A{beta}, MAP2, phos-Tau, Cathepsin D, Sortilin 1, Ceruloplasmin and Hemin. Firstly, we confirmed that senile plaque A{beta} deposition mostly happened in MAP2-positive but degenerative neuritic processes. Secondly, we found an interesting dual-component granular or diffusive staining pattern of all of these senile plaque related markers, matching to two states of lysosomes, relatively-stable granule lysosomes and destabilized diffusive lysosomes as shown by lysosome-related marker Cathepsin D or Sortilin 1 staining. Thirdly, dystrophic senile plaque neural processes contain hemorrhage-related markers such as Ceruloplasmin and Hemin. In addition, A{beta} deposition, Tau phosphorylation, lysosome destabilization are all enriched at the sites of microaneurysm formation. Moreover, senile plaques are also characterized by a widespread binary phos-Tau staining pattern with difference in term of staining intensity. We concluded that senile plaques are formed by destabilized-lysosome-enriched neural processes catabolizing extracellular hemorrhagic amyloid materials, with microaneurysm as an important intermediate stage.

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Fu, H., Li, J., Zhang, C., Gao, G., Ge, Q., Cui, D.. 2025-12-30. The biochemical nature of senile plaques: intracellular destabilized-lysosome-enriched neural processes catabolizing extracellular hemorrhagic amyloid materials. https://doi.org/10.64898/2025.12.30.696965

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