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Fred Oliveira-Souza, Mark Bolding, Marci L DeRamus, Thomas vanGroen, Christianne E Strang; Changes in the Retinal Cholinergic System (RCS) in the Tg-SwDI Alzheimer’s Disease Mouse Model. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1761.
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© 2017 Association for Research in Vision and Ophthalmology.
Alzheimer’s disease (AD), the most common type of dementia, is characterized by severe cognitive deficits, which may arise as a result of tauopathy, senile plaques, substantial neuronal loss and abnormalities of several neurotransmitter systems (e.g. cholinergic). Impairment in motion perception, contrast sensitivity, acuity and color are also present in AD. We believe that these visual deficits may stem from disturbances in the RCS. To assess this hypothesis, we compared acetylcholine receptor (AChR) transcript expression in the retinas of Tg-SwDI mice in three age groups: 6-8.9, 9-11.9 and 12-15 months old (mo). Tg-SwDI mice express the human amyloid precursor protein with the Swedish KM670/671NL, Dutch E693Q, and Iowa D694N mutations.
We conducted quantitative real-time polymerase chain reaction (qPCR) with validated and optimized primers using whole-retina RNA.
We observed statistically significant (≤0.05) differences in all age groups, in nicotinic (nAChR) and muscarinic (mAChR) mRNA transcripts in the retinas of AD mice as compared to age-matched wild type (WT) mice; fold-change is shown in parentheses. At 6-8.9 mo, there was upregulation (UR), in α2 (3.7), α4 (2.7), α5 (2.4), α6 (1.9), α7 (2.5), β3 (2.4) and β4 (3.0) nAChR subunits; and downregulation (DR) in α9 (3.2) and α10 (7.1) nAChR subunits, m4 (2.6) and m5 (6.1) mAChRs. At 9-11.9 mo, there was UR in m1 mAChR (13.3) and in α2 (14.5), α3 (19.3), α4 (8.7), α5 (6.5), α6 (19.3), α9 (4.7), β3 (3.8) and β4 (5.2) nAChR subunits. They also exhibited DR in α10 nAChR subunit (4.9) and m5 mAChR (8.5). At 12-15 mo, there was DR in m4 (3.3) and m5 (5.8) mAChRs, α4 (5.1), α7 (3.8), α9 (6.3) and α10 (7.9) nAChR subunits.
The early UR of AChR transcripts might compensate, in part, for the loss of cholinergic cells. As the cell loss becomes extensive, this compensatory mechanism can no longer mitigate the cholinergic deficits. Knowing the causes of the visual deficits may be crucial in early AD diagnosis, as they may occur before cognitive decline is observed. The retina provides an enormous opportunity to develop non-invasive biomarkers for AD and early diagnosis through visual assessment. This work is an important step in the quest towards attaining a better understanding of AD and facilitating its early detection and treatment.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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