Cross talk between tau hyperphosphorylation and impaired brain glucose metabolism: an implication for Alzheimer's disease

In a past decade's neurofibrillary tangles (NFTs) and Aβ plaques has spotted in brain-specific region as a hallmark of AD, that gradually causes cognitive impairment. PET analysis together with biochemical analysis has confirmed the significance of NFTs and plaques in the AD pathology but we further need to strength on the causes that lead to cognitive impairment before it distinguishes in severe AD symptoms. Interestingly, Insulin resistance together with impaired glucose metabolism and increased ROS production in the brain has been linked with AD development (Barone, E., 2011a; 2011 b; 2014, and 2015; Butterfield, D. A., 2014; Hart, G. W., 2011). These alterations in the signaling pathways have seen very often in a large population of old people with increasing in numbers every year. Thus, in the current situation, the biggest challenge is not only to discover the biomarkers but also to understand the molecular mechanism of pathology at early-onset AD and late-onset as well. For the first time, the link between oxidative stress and impaired glucose transport has been evidenced in cultured neurons, which is followed by a decrease in cellular ATP levels due to a dysfunctional respiratory chain reaction in mitochondria (Keller, J. N.,1997; Luo, Y., 1997). Further studies suggested that altered glucose metabolism is a very early change in the AD (De Leon, M. J., 2001; Mosconi, L., 2008; Small, Gary W., 1995; Reiman, E. M., 1996; Mosconi, L., 2006) and legitimately correlates the clinical disabilities with dementia (Blass, J. P., 2002). The occurrence of insulin resistance in early AD due to impaired glucose metabolism concomitantly stimulates the oxidative stress in the AD brain and have recognized as early symptoms. This alteration can be an indication for the transition of pre-clinical AD (PCAD) to the MCI stage. Although one study suggests that OS occurs before the onset of AD symptoms and that oxidative damage is found before robust Aβ plaque formation (Butterfield, D. A., 2014). Thus, insulin resistance, oxidative stress, and impaired glucose metabolism promotes a feedback mechanism and involved as a vicious cycle in the early phase of AD development. It is known that OS and impaired brain metabolism affects downstream targets; i) GSK-3β and, ii) BVR-A/HO-1, which plays a significant role in several signaling and among all OS mediated Akt activation and GSK-3β inhibition is a part of neuroprotective mechanism in the AD brain (Talbot, K., 2012; Steen, E., 2005; Rivera, E. J., 2005; Zhang, X., 2016; Morales-Corraliza, J., 2016; Sajan, M. P., 2016; Yarchoan, M., 2014; Bomfim, T. R., 2012; Butterfield, D. A.,2014). When it comes to understand the role of HO-1/BVR-A system in the AD, one of the studies from Butterfield and the group has been reported an astonishing observation which revealed that oxidative/nitrosative post-translation modification of HO/BVR system associated with its decreased phosphorylation forms (BVR-A activity) in MCI and AD brain (Barone E 2011a and 2011b). On the other hand, based on its scaffold properties, another study from Maines group has reported the BVR-A/Akt mediated GSK-3β activation (Miralem, T., 2016) and also data from our group showed that BVR-A plays a significant role as a scaffold protein in CK1 mediated BACE-1 phosphorylation and resulting in Aβ depositions in aging model (Triani, F., 2018). So further BVR-A is a central attraction in my study because previously our group has shown that reduced total BVR-A level and its activity proportionally associated with the increased levels of OS in AD and MCI brain (Barone, E., 2011a; Barone, E., 2011b; Barone, E., 2014) and 3xTg-AD mice (Barone, E., 2016). Therefore, it would be surprising if downstream target i.e., Akt and GSK-3β get affected by reduced BVR-A levels, instead of by merely insulin resistance-mediating signaling. Alteration in BVR-A associated signaling may further lead to the development of tauopathy in AD brain through GSK-3β regulation which is a prominent kinase for Tau hyperphosphorylation. Therefore, while the presence of BVR-A in the human brain could contribute in several kinases (i.e., GSK-3β) mediated or scaffold-mediated signaling i.e., BVR-A/Akt and BVR-A/CK1, we further hypothesized that its impairment could prevent those regulatory implications and leads to pathology in the brain including insulin resistance and Alzheimer disease. To the betterment of our understanding in AD pathology, in our first project, we combine all the previous observation and propose the role of BVR-A in Akt-mediated GSK-3β inhibition. We hypothesize that the loss of BVR-A could prevent the BVR-A/Akt complex formation and the Akt mediated GSK-3β inhibition which may lead to Tau hyperphosphorylation in the AD brain. To this aim we performed our experiments with; i) 3xTg-AD mice (AD mice model) /Non-Tg mice at the early age (6 months) and late age (12 months); ii) Human MCI and AD subjects and iii) in-vitro HEK cells. Moreover, early insulin resistance and BVR-A impairment further causes a reduction in glucose availability to the brain and lasts till the late phase in the AD. Less glucose consumption favors impairment of HBP pathway and glycosylation; a typical post-translation modification (PTM) that responsible for protein functionalities. Interestingly, glycosylation and phosphorylation share the same target site (Ser/Thr) on protein in a reciprocal manner. Speaking about AD, dysregulation of any of these PTM indicates the pathophysiological status of the AD brain. Several preceding studies were focused on understanding the crosstalk between phosphorylation and O-GlcNAcylation in disease pathophysiology as they compete for the same site (Hart, G. W., 1997). Recent advanced proteomic that includes the selective enrichment of low -abundance O-GlcNacylated species (proteins) from a complex mixture, followed by high-technology mass spectrometric (MS) method have allowed the mapping and quantification of multiple O-GlcNAcylation sites (Khidekel, N., 2007). This proteomic analysis suggests that O-GlcNAcylation parallels phosphorylation concerning all dynamics, abundance, and impact on protein function. On the basis of these observations, we can presume that limited glucose uptake (impaired glucose metabolism) veils the occurrence of O-GlcNAcylation but would slightly increase the chances of phosphorylation. These results, with the agreement of our first hypothesis, would further clarify the accumulation of hyperphosphorylated Tau in AD brain. Therefore, further our interest focused on brain glucose impairment in late phase AD and to understand the crosstalk between phosphorylation and glycosylation in AD pathology. With the help of a proteomic approach, in the second study, we identified and validated O-GlcNAcylated proteins involved in different pathways and pathologies (i.e. Alzheimer). In our second project, we highlight the synergistic relationship between phosphorylation and glycosylation to reveal the involvement of impaired brain glucose metabolism in Tau like pathology in AD brain.