Development and Expression of Amyloid‐β Peptide 42 in Retinal Ganglion Cells in Rats

Abstract

The previous studies have shown that Amyloid-b peptide (Ab) was mainly found in neurons of neurodegenerative diseases, such as Alzheimer's disease (AD) and glaucoma and little is known about its expression in normal nerve cells. The aim of the present study was to investigate the expression of amyloid-b peptide 42 (Ab-42) in retinal ganglion cells of the postnatal rats. Rats were divided into seven experimental groups: 3, 6, 13, 15, 25, 60, and 90 days postnatal groups. Rats from 15 and 25 days postnatal groups were further divided into light-exposure and non light-exposure group. Cryosections or flat-mounted retinas of rat eyes were used for testing Ab-42 by immunocytochemistry staining. Ab-42 expression was not observed in rats within 13 days after birth, but was easily detectable in all groups of rats over 15 days after birth. In addition, the expression of Ab-42 in retina was increasing as the rats got older, reached to highest level in 60 days after birth. Furthermore, the expression of Ab-42 was not detected in rats kept under dark indicating that light is required for the expression of Ab-42 in retina. This is the first report showing that normal retinal ganglion cells express Ab-42, and that the expression of Ab-42 in retinal ganglion cells requires the exposure to light. These data suggest that Ab-42 may play a important role in vision development. Anat Rec, 294:1401-1405, 2011. V V C 2011 Wiley-Liss, Inc.Key words: amyloid-peptide 42; retinal ganglion cells; visual development; rat; immunocytochemistry Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive loss of memory. A hallmark feature of the AD is the formation of senile plaque (Selkoe, 1994 andFrost et al., 2003), in which amyloid-bpeptide 42(Ab-42) plays a central role (Selkoe, 2004). It was reported that the level of Ab-42 in aqueous humor of glaucoma patients was significantly higher than that of normal people (Blanks et al., 1989).A wealth of studies has demonstrated that Ab-42 is highly toxic to cultured retinal ganglion cells. Exogenously administrated Ab-42 induces apoptosis of the retinal ganglion cells in rats in vivo (Hinton et al., 1986;Yoshida et al., 1997; Alvarez et al., 1998), therefore, it is assumed that normal retinal ganglion cells do not express Ab-42. We currently investigated the expression of Ab-42 in retinal ganglion cells in rat by using immunocytochemistry. Results from our studies indicate that Ab-42 is expressed by retinal ganglion cells in rats, and the expression is dependent on the exposure to light.

The Alzheimer's-related amyloid beta peptide is internalised by R28 neuroretinal cells and disrupts the microtubule associated protein 2 (MAP-2)

“…Although APP/Aβ immunoreactivity was previously reported in whole retinal mounts, in RGC, the inner nuclear layer and on photoreceptors (Dasari et al., 2011, Dutescu et al., 2009, Guo et al., 2007, Hoh et al., 2010, Kipfer-Kauer et al., 2010, Koronyo-Hamaoui et al., 2011, Wang et al., 2011), we wanted to establish whether a predetermined amount of physiological Aβ 1-42 was realistically capable of localising to the living retina. To assess if this was possible, ∼2 μl of oligomeric of Aβ 1-42 (625 nM) was subretinally injected into C57BL/6 wildtype mice to recapitulate the elevated Aβ burden reported in aged and AMD retinas (Ratnayaka et al., 2015).…”

“…Similar findings by other groups revealed that Aβ also activated the complement system to bring about a state of chronic inflammation in subretinal tissues (Catchpole et al., 2013, Koyama et al., 2008, Wang et al., 2008, Wang et al., 2012b, Yoshida et al., 2005). However, retinal neurons are also immunopositive for APP/Aβ (Dasari et al., 2011, Dutescu et al., 2009, Guo et al., 2007, Hoh et al., 2010, Kipfer-Kauer et al., 2010, Koronyo-Hamaoui et al., 2011, Wang et al., 2011), suggesting that Aβ activity is not exclusive to the RPE. Therefore, to fully understand how Aβ could impair the senescent eye, it was important to study whether the neuroretina is also affected by this neurotoxic group of peptides.…”

“…Our studies focused on oligomeric Aβ 1-42 ; as this highly neurotoxic and aggregate-prone Aβ species has been the focus of considerable work in neurodegeneration (Benilova et al., 2012, Soura et al., 2012). As neurons in the central nervous system are known to secrete small soluble Aβ forms (Benilova et al., 2012, McLean et al., 1999), we reasoned that this was also likely to be the case in the retina, particularly as some retinal neurons are immunopositive for APP/Aβ (Dasari et al., 2011, Dutescu et al., 2009, Guo et al., 2007, Koronyo-Hamaoui et al., 2011, Wang et al., 2011). The use of antibodies that cannot distinguish between APP vs. Aβ in past studies (Dasari et al., 2011, Wang et al., 2011) have resulted in some confusion.…”

“…For example, Aβ immunoreactivity was reported in retinal ganglion cells (RGC) of mice (Guo et al., 2007) and in the inner nuclear layer and RGC of rabbits (Dasari et al., 2011), whilst curcumin positive Aβ plaques were observed in retinal whole-mounts of AD patients (Koronyo-Hamaoui et al., 2011). This was not surprising as some retinal neurons express the amyloid precursor protein (APP) (Dutescu et al., 2009, Wang et al., 2011); the precursor form from which Aβ is cleaved (Benilova et al., 2012). Aβ 1-42 , which is considered to be the most pathogenic and aggregate-prone of the Aβ species (Citron et al., 1997), was shown to increase in RGC with increasing age (Wang et al., 2011).…”

“…This was not surprising as some retinal neurons express the amyloid precursor protein (APP) (Dutescu et al., 2009, Wang et al., 2011); the precursor form from which Aβ is cleaved (Benilova et al., 2012). Aβ 1-42 , which is considered to be the most pathogenic and aggregate-prone of the Aβ species (Citron et al., 1997), was shown to increase in RGC with increasing age (Wang et al., 2011). This observation is consistent with evidence that senescent RPE also produce increasing levels of Aβ (Yoshida et al., 2005).…”