App Involvement In Retinogenesis

Abstract

Purpose: : The amyloid precursor protein (APP), expressed most abundantly in the brain, is known to play, together with its proteolytic fragments, numerous and varied roles in cell physiology and pathology, including in Alzheimer disease (AD). Amyloid beta, the main proteolytic fragment of APP has been recently detected in retinas of AD patients.Our understanding of APP's normal functions remains however very limited. We therefore investigated the spatiotemporal patterns of expression and the roles of APP in the mice developing neuroretina and in adults.

Methods: : We identified the cell types that expressed APP by PCR, in situ hybridization and immunochemistry. APP knockout mice were used to define the functional role of APP in retinal cell differentiation. To determine the mechanism of action of APP, retinal differentiation and APP expression were investigated in mice knocked out for sorLA, a recently identified regulator of APP.

Results: : APP695, APP751 and APP770 are expressed in the mouse retina from embryonic stage through adulthood. APP mRNA and protein are expressed according to the different waves of retinal differentiation. Depletion of App led to alteration of the inner synaptic layer, only half as many glycinergic amacrine cells and a 50% increase in the number of horizontal cells. We identified Ptf1a as a downstream effector of APP. A similar phenotype in mice knocked out for sorLA was observed.

Conclusions: : APP functions through sorLA to control the determination of AII amacrine and horizontal cell fate. These findings provide novel insights that indicate that APP plays an important role in retinal differentiation.

Keywords: development • inner retina dysfunction: biochemistry and cell biology • retina: proximal (bipolar, amacrine, and ganglion cells)