Concomitant Retinal Alterations in Neuronal Activity and TNF alpha Pathway Are Detectable during the Pre-Symptomatic Stage in a Mouse Model of Alzheimer's Disease

The pre-symptomatic stage of Alzheimer's disease (AD) is associated with increased amyloid-beta (A beta) precursor protein (APP) processing and A beta accumulation in the retina and hippocampus. Because neuronal dysfunctions are among the earliest AD-related alterations, we asked whether they are already detectable in the retina during the pre-symptomatic stage in a APPswePS1dE9 (APP/PS1) mouse model. The age chosen for the study (3-4 months) corresponds to the pre-symptomatic stage because no retinal A beta was detected, in spite of the presence of beta CTF (the first cleavage product of APP). We observed an increase in ERG amplitudes in APP/PS1 mice in comparison to the controls, which indicated an increased retinal neuron activity. These functional changes coincided with an increased expression of retinal TNF alpha and its receptors type-1 (TNFR1). Consistently, the IkB expression increased in APP/PS1 mice with a greater proportion of the phosphorylated protein (P-IkB) over total IkB, pointing to the putative involvement of the NFkB pathway. Because TNF alpha plays a crucial role in the control of neuronal excitability, it is likely that, as in the hippocampus, TNF alpha signaling via the TNFR1/NFkB pathway may be also involved in early, AD-associated, retinal neuron hyperexcitability. These results further demonstrate the interest of the retina for early disease detection with a potential to assess future therapeutic strategies.