Cystatin C and Amyloid Pathology in Neurodegenerative Diseases

Cystatin C is a ubiquitous cysteine protease inhibitor expressed in the brain, cerebrospinal fluid and peripheral tissues. In neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and cerebral amyloid angiopathy, accumulation of amyloid β (Aβ) peptides in neural parenchyma or vessel walls is a defining feature. Cystatin C binds directly to Aβ, inhibiting its oligomerisation and fibril formation, and co-localises with amyloid deposits in both human post-mortem tissue and animal models. Beyond direct binding, cystatin C modulates amyloid precursor protein processing, shifts secretion towards non-amyloidogenic pathways and induces autophagy via mTOR inhibition, enhancing clearance of aggregated proteins. Genetic variants in the CST3 gene are linked to altered cystatin C expression and increased Alzheimer’s disease risk. Clinically, elevated serum cystatin C levels correlate with declines in processing speed, memory and executive function, as well as a higher prevalence of mild cognitive impairment and dementia. Together, mechanistic and population studies position cystatin C as both a biomarker of early cognitive decline and a potential therapeutic target for modifying amyloid pathology and neurodegeneration.

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Cystatin C and Amyloid Pathology in Neurodegenerative Diseases publication trend

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Technical terms

Cystatin C: A small, secreted inhibitor of cysteine proteases involved in protein turnover and clearance of aggregated peptides.

Amyloid β (Aβ): Peptide fragments derived from amyloid precursor protein that aggregate into oligomers and fibrils implicated in neurodegeneration.

Mild cognitive impairment (MCI): A transitional stage characterized by measurable cognitive deficits not severe enough to interfere substantially with daily life.

Autophagy: A regulated cellular pathway that degrades and recycles damaged organelles and misfolded proteins through lysosomal machinery.

mTOR pathway: A central regulator of cell growth and autophagy, where inhibition promotes clearance of aggregated proteins.

Protease: An enzyme that cleaves peptide bonds in proteins, whose activity can be regulated by endogenous inhibitors like cystatin C.

References

1. Cystatin C in Alzheimer's disease. Frontiers in Molecular Neuroscience (2012).
2. Cystatin C Shifts APP Processing from Amyloid-β Production towards Non-Amyloidgenic Pathway in Brain Endothelial Cells. PLOS ONE (2016).
3. Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines. PLOS ONE (2010).
4. Serum cystatin C and mild cognitive impairment: The mediating role of glucose homeostasis. Frontiers in Aging Neuroscience (2023).
5. Association between serum cystatin C level and cognition in older adults: a cross-sectional analysis. Frontiers in Neuroscience (2023).