They have shown that serine racemase/D-serine promotes DR and inactivation of SR protects against neurodegeneration in DR. Recently, they indicated that injection of virus expressing D-amino acid oxidase before the onset of diabetes prevents neurovascular abnormalities in DR. Refer to : Journal of Neuroinflammation,2011,8:119; Experimental Eye Research,2018 Oct;175:90-97; Diabetologia, 2020 (DOI: 10.1007/s00125-020-05333-y).
2.Molecular mechanism underlying synapse loss and neurodegeneration in Alzheimer’s disease
They have shown that autophagic degradation of STIM1 or STIM2 may underlie synapse loss in the conditions linked with Alzheimer’s disease.
Neuronal SOCE is disrupted in SAD and FAD and the possible mechanism. Neuronal SOCE is attenuated in AD, yielding instability of neuronal dendrite spines. 1, In healthy neurons(green color), while ER Ca2+ is depleted, STIM proteins are induced to form calcium-influx channel with CRAC channels such as ORAI or/and TRPC. 2, SOCE deficiency leads to inactivation of calcium-calmodulin dependent kinase II which regulates phosphorylation of CREB and its entry into nucleus. Activation of CREB results in transcription of BDNF, c-Fos, and synaptotagmin-IV; these effects play crucial roles in learning and memory. 3 and 4, AD-related stresses such as sublethal levels of proteasome inhibition or ER stresses activate autophagy, which degrades STIM1 or STIM2, thereby attenuating SOCE. 5,SOCE inhibition leads to reduction of cytosolic calcium which reduces p-CaMKII and p-cofilin, thereby inducing cytoskeleton disassembly and dendrite degeneration. 6, In FAD, enhanced γ-secretase activity of Presenilin1 mutant increases cleavage of STIM1 transmembrane domain, thus leading to attenuation of nSOCE and disruption of dendrite spine. 7, Presenilin forms a Ca2+ leak channel in ER; FAD-associated Presenilin mutant fails to function as a Ca2+ leak channel, resulting in expansion of ER calcium pool, thereby failing to initiate SOCE. 8 and 9, AD-related Presenilin1 mutant down-regulates formation of STIM2-TRPC6-Orai2 complex, leading to disruption of STIM2-nSOCE and loss of mushroom spines. Refer to: Current Alzheimer’s Research,2020 (accepted); Journal of Neurochemistry, 2019 Nov;151(3):351-369.
2.They have found that Dicer1 is reduced in the brain of AD mice which is the first report
to examine Dicer1 in AD. They further found (i) that Aβ42 exposure decreases Dicer1 via attenuating Nrf2-ARE signaling and (ii) injection of Dicer1-expressing adenovirus into the hippocampus of the AD mice significantly improves spatial learning. Altogether, they found novel roles of Dicer1 in AD and a novel regulatory pathway for Dicer1. This study may open new avenues for investigating potential pathognomonics and pathogenesis in AD. Refer to: Molecular Neurobiology, 2020 Nov;57(11):4417-4437.
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