Dysfunction of the glutamatergic photoreceptor synapse in the P301S mouse model of tauopathy

Abstract

Tauopathies, including Alzheimer’s disease, are characterized by retinal ganglion cell loss associated with amyloid and phosphorylated tau deposits. We investigated the functional impact of these histopathological alterations in the murine P301S model of tauopathy. Visual impairments were demonstrated by a decrease in visual acuity already detectable at 6 months, the onset of disease. Visual signals to the cortex and retina were delayed at 6 and 9 months, respectively. Surprisingly, the retinal output signal was delayed at the light onset and advanced at the light offset. This antagonistic effect, due to a dysfunction of the cone photoreceptor synapse, was associated with changes in the expression of the vesicular glutamate transporter and a microglial reaction. This dysfunction of retinal glutamatergic synapses suggests a novel interpretation for visual deficits in tauopathies and it highlights the potential value of the retina for the diagnostic assessment and the evaluation of therapies in Alzheimer’s disease and other tauopathies.

Immunotherapy with Cleavage-Specific 12A12mAb Reduces the Tau Cleavage in Visual Cortex and Improves Visuo-Spatial Recognition Memory in Tg2576 AD Mouse Model

“…Taken together, these results show for the first time that the cleavage at the N-terminal tau with the release of diagnostic 20–22 kDa toxic neuropeptide (i.e.,NH 2 htau) is not only restricted to the retina and associated ocular structures of 6-month-old Tg2576 AD mice [ 12 ], but is also extended to their primary visual cortex (V1 area), in agreement with studies reporting that the accumulation of other pathogenic misfolded and/or hyperphosphorylated tau species is detectable along the entire visual system both in different preclinical AD animal models and AD subjects [ 7 , 79 , 80 , 81 , 82 , 83 ]. More importantly, the NH 2 htau fragment is successfully immunodepleted in the V1 area by 12A12mAb administration, which also exerts an anti-amyloidogenic effect by reducing the local expression levels of APP/Aβ ( Supplementary Figure S1 ), just as we reported to occur in the hippocampus and in the retina of this transgenic strain [ 12 , 42 ].…”

Scientific commentary on: “Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer’s disease and primary tauopathies”

“…After reading Hart de Ruyter et al [ 5 ], we decided to quantify thickness changes of the IPL, OPL, and INL in tauopathies compared with healthy controls (HCs) and non-tau-related pathologies in 4RTNI. We also quantified changes in the outer nuclear layer (ONL)—which contains the cell bodies of rod and cone photoreceptors—in line with a recent publication by Arouche-Delaperche that described functional impairment directly due to tau deposition and indirectly due to tau-associated microglial activation in animal models of tauopathy [ 2 ]. We further investigated changes in the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell layer (GCL), which contain the axons and cell bodies of retinal ganglion cells, respectively, and are of interest as markers of neurodegeneration [ 4 ].…”

“…Ganglion cell loss was not investigated by Hart de Ruyter et al [ 5 ], but was shown recently by Arouche-Delaperche in a tauopathy animal model [ 2 ]. The absence of GCL thinning in our subset analysis of patients ≤ 5 years since onset suggests that ganglion cell loss and therefore retinal neurodegeneration occur later in the disease.…”