Early proteomic signatures of Alzheimer's disease in the retina and brain of 3xTg-AD mice.

INTRODUCTION

Visual dysfunction and retinal structural changes can occur early in Alzheimer's disease (AD), but the molecular basis of these early alterations remains unclear.

METHODS

We performed quantitative proteomic profiling of the retina and brain from 4-week-old triple-transgenic AD (3xTg-AD) mice carrying human PS1M146V, APPSwe, and tauP301L mutations, prior to detectable retinal morphological abnormalities.

RESULTS

Retinal morphology was normal in 4-week-old 3xTg-AD. Proteomic analysis identified 92 significantly altered proteins in the retina and 130 in the brain, with eight proteins overlapping between tissues. These overlapping proteins included three hemoglobin subunits and five proteins involved in protein homeostasis and vesicular transport. The retinal proteome was characterized by reduced vision-related proteins, altered small-molecule transporters, and decreased levels of proteins involved in mitochondrial energetics. In the brain, prominent changes were observed in mitochondrial proteins, including respiratory chain components and mitochondrial ribosomal subunits, as well as proteins linked to autophagy and synaptic vesicle pathways.

DISCUSSION: These findings identify early, common and tissue-specific proteomic changes in the retina and brain of 3xTg-AD mice prior to detectable retinal structure abnormalities. The data indicate early changes in proteins related to mitochondrial function and intracellular transport and support the use of retina as an accessible tissue for detecting preclinical AD pathology.