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Basic Science and Pathogenesis.

Altan Rentsendorj1, Dieu-Trang Fuchs2, Jean-Philippe Vit1

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Summary
This summary is machine-generated.

Alzheimer's disease (AD) pathology affects the retina, causing synaptic loss and reduced UCH-L1 levels. These changes correlate with cognitive decline and brain pathology, suggesting UCH-L1's potential as an AD biomarker.

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Area of Science:

  • Neuroscience
  • Ophthalmology
  • Biochemistry

Background:

  • Alzheimer's disease (AD) pathology extends to the retina, impacting neurosensory function.
  • Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is implicated in AD brain pathology but its retinal role is unknown.

Purpose of the Study:

  • To investigate UCH-L1 expression in the retina and its relationship with synaptic integrity and cognitive function in Alzheimer's disease.
  • To explore the retina as a potential site for AD biomarkers.

Main Methods:

  • Immunohistochemistry and mass spectrometry were used to analyze postmortem retinas from AD, mild cognitive impairment (MCI), and control individuals.
  • Retinal markers of synaptic integrity and UCH-L1 levels were quantified and correlated with brain pathology (Braak, ABC scores) and cognitive function (MMSE, CDR scores).
  • AI-based Random Forest analysis identified key predictors of disease status.

Main Results:

  • Significant synaptic loss (pre- and post-synaptic markers) was observed in the inner and outer plexiform layers of MCI and AD retinas.
  • Levels of membrane-associated UCH-L1 (UCH-L1M) were significantly reduced in MCI and AD retinas.
  • Retinal synaptic loss and UCH-L1M decline strongly correlated with amyloid-beta (Aβ), phosphorylated tau, cognitive impairment, and AD brain pathology.

Conclusions:

  • Early and substantial synaptic loss and UCH-L1M decline occur in the retinas of individuals with MCI and AD.
  • UCH-L1M is a significant predictor of tauopathy progression and cognitive impairment, suggesting its potential as a biomarker for AD detection.
  • UCH-L1M may also represent a therapeutic target for AD.