Available evidence suggests that the retina may be used as a window to study neurodegeneration in Alzheimer’s disease (AD). Peroxisome proliferator activated receptor alpha (PPAR-α) is a member of ligand-regulated nuclear receptors (PPARs). Of importance, PPAR-α regulates expression of genes coding enzymes engaged in Alzheimer’s amyloid precursor protein (APP) metabolism. In AD brain expression of genes of PPAR-α and PPAR-γ coactivator-1 alpha (PGC-1α) is significantly decreased. We have identified AATF (apoptosis antagonizing transcription factor) as a neuroprotective protein. Both PPAR-α and AATF are nuclear transcription proteins involved in neuroprotection. Using the triple-transgenic mouse model of AD (3×Tg-AD) that expresses three major genes associated with familial AD, namely APPswe, PS1M146V, and tauP301L, we will test the hypothesis that AATF interacts with PPAR-α and forms a transcription complex to activate neuroprotective transcriptions in the nucleus of retinal neurons, and that a decrease/loss in PPAR-α activation and function in retinal ganglion cells (and potentially in other retinal cells including photoreceptors and bipolar cells, etc.) is an early indicator of neuronal degeneration in AD. We will also investigate if targeted delivery of small AATF core peptides across the blood-retinal barrier translates into a viable therapy for retinal degeneration in AD.