Neurodegeneration in type 2 diabetes: Alzheimer's as a case study.

INTRODUCTION: Rigorous research in the last few years has shown that in addition to the classical mechanism of neurodegeneration, certain unconventional mechanisms may also lead to neurodegenerative disease. One of them is a widely studied metabolic disorder: type 2 diabetes mellitus (T2DM). We now have a clear understanding of glucose-mediated neurodegeneration, mostly from studies in Alzheimer's disease (AD) models. AD is recognized to be significantly associated with hyperglycemia, even earning the term "type 3 diabetes." Here, we review first the pathophysiology of AD, both from the perspective of classical protein accumulation, as well as the newer T2DM-dependent mechanisms supported by findings from patients with T2DM. Secondly, we review the different pathways through which neurodegeneration is aggravated in hyperglycemic conditions taking AD as a case study. Finally, some of the current advances in AD management as a result of recent research developments in metabolic disorders-driven neurodegeneration are also discussed. METHODS: Relevant literatures found from PubMed search were reviewed. RESULTS: Apart from the known causes of AD, type 2 diabetes opens a new window to the AD pathology in several ways. It is a bidirectional interaction, of which, the molecular and signaling mechanisms are recently studied. This is our attempt to connect all of them to draw a complete mechanistic explanation for the neurodegeneration in T2DM. Refer to Figure 3. CONCLUSION: The perspective of AD as a classical neurodegenerative disease is changing, and it is now being looked at from a zoomed-out perspective. The correlation between T2DM and AD is something observed and studied extensively. It is promising to know that there are certain advances in AD management following these studies.

Adult Goat Retinal Neuronal Culture: Applications in Modeling Hyperglycemia.

Culture of adult neurons of the central nervous system (CNS) can provide a unique model system to explore neurodegenerative diseases. The CNS includes neurons and glia of the brain, spinal cord and retina. Neurons in the retina have the advantage of being the most accessible cells of the CNS, and can serve as a reliable mirror to the brain. Typically, primary cultures utilize fetal rodent neurons, but very rarely adult neurons from larger mammals. Here, we cultured primary retinal neurons isolated from adult goat up to 10 days, and established an in vitro model of hyperglycemia for performing morphological and molecular characterization studies. Immunofluorescence staining revealed that approximately 30-40% of cultured cells expressed neuronal markers. Next, we examined the relative expression of cell adhesion molecules (CAMs) in adult goat brain and retina. We also studied the effect of different glucose concentrations and media composition on the growth and expression of CAMs in cultured retinal neurons. Hyperglycemia significantly enhances neurite outgrowth in adult retinal neurons in culture. Expression of CAMs such as Caspr1, Contactin1 and Prion is downregulated in the presence of high glucose. Hyperglycemia downregulates the expression of the transcription factor CCAAT/enhancer binding protein (C/EBP α), predicted to bind CAM gene promoters. Collectively, our study demonstrates that metabolic environment markedly affects transcriptional regulation of CAMs in adult retinal neurons in culture. The effect of hyperglycemia on CAM interactions, as well as related changes in intracellular signaling pathways in adult retinal neurons warrants further investigation.