Research Paper Volume 16, Issue 10 pp 9072—9105

Figure 5. The relationship between the process of substrate translocation into lysosomes during CMA and dementia degree. (A–D) detail the correlation between gene expression levels and the Mini-Mental State Examination (MMSE) scores, which serve as a clinical measure of dementia severity, with lower MMSE scores indicating more severe dementia. The vertical axis denotes MMSE scores, while the horizontal axis captures gene expression levels. (E–H) explore the link between gene expression levels and the count of Neurofibrillary Tangles (NFTs), markers of neurodegeneration. The underlying molecular mechanism across these subfigures highlights that CMA’s role in degrading substrates—generally abnormal proteins—is triggered by substrate accumulation. Excessive accumulation of such proteins results in proteotoxicity, correlating with increased dementia severity. Subfigure B demonstrates that lower expression of HSP90AB1 aligns with reduced MMSE scores and heightened dementia severity. HSP90AB1 functions as an inhibitory protein; its reduced expression facilitates the unfolding of abnormal proteins, easing their entry into the LAMP2A complex and thus activating CMA. Consequently, lower levels of HSP90AB1 indicate enhanced CMA activity. Subfigures A and D show that higher expressions of GFAP or LAMP2 correlate with lower MMSE scores and increased dementia severity. The GFAP-LAMP2A complex is essential for delivering substrates to the lysosome, and its activation is prompted by the overaccumulation of abnormal proteins. The presence of more severe dementia suggests greater protein accumulation, leading to increased activity of the GFAP-LAMP2A complex and elevated expression of both GFAP and LAMP2. Upon completion of substrate delivery, the protein encoded by EEF1A1 disassociates GFAP, resetting the LAMP2A complex to its initial state, as depicted in subfigure C. Higher levels of EEF1A1, indicating lower MMSE scores and greater dementia, underscore its role in concluding the delivery process and reinstating CMA’s baseline functionality. Overall, the sensitivity of the process of substrate translocation into lysosomes during CMA to AD progression mirrors the degree of dementia, offering a reflective measure of dementia severity. This comprehensive analysis is further detailed in Conclusion and illustrated in Figure 6.