Advanced glycation endproducts, AGEs, build up in tissues over time as a natural consequence of the operation of metabolism. The detrimental effects that AGEs have on tissue integrity and cellular behavior contribute to degenerative aging - their presence is a form of damage. Some attempts have been made in past years to develop drugs to safely break down AGEs, but little progress has been made. The types of AGE important in humans are quite different from those that matter in rodents, and so promising animal studies went nowhere. At the present time the research community lacks the tools to work with the most common AGE in humans, glucosepane, and the SENS Research Foundation is one of the very few groups trying to do something about this.
This research group shows some of the harm caused by AGEs in brain tissue, and notes that it depends on the presence of the receptor for AGEs, RAGE, which is much as expected. They then take the expected route for mainstream science, proposing an alteration to the operation of cells to block or remove RAGE so as to reduce the impact of AGEs, rather than proposing removal of the AGEs. This sort of inefficient focus on consequences and proximate causes rather than root causes is very common in modern medical research, and it needs to change.
Synaptic dysfunction and degeneration is an early pathological feature of aging and age-related diseases, including Alzheimer's disease (AD). Aging is associated with increased generation and deposition of advanced glycation endproducts (AGEs), resulting from nonenzymatic glycation (or oxidation) of proteins and lipids. AGE formation is accelerated in diabetes and AD-affected brain, contributing to cellular perturbation.
In addition to its ability to directly alter the structure and function of targeted proteins within cells that causes cell or tissue damage, emerging evidence has also demonstrated AGEs as a signaling ligand, interacting with RAGE; AGEs elicit signal transduction changes that adversely affect numerous peripheral organs. Although AGE accumulation is increased in cortical neurons, hippocampal pyramidal neurons, astrocytes, and other glial cells in aging and AD brain, the direct effect of AGEs-RAGE interaction on brain function, in particular on changes in synaptic structure and function, remains largely unknown.
Using our novel transgenic mouse model with neuronal expression of RAGE signaling and lacking neuronal RAGE in the forebrain for evaluation of synaptic transmission and plasticity (almost every brain function relays on synaptic transmission), we provide convincing evidence to support a pivotal role of neuronal AGEs-RAGE interaction on MAPK P38 activation, hippocampal plasticity deficit, and synaptic injury. Addition of AGEs to brain slices impaired hippocampal long-term potentiation (LTP). Similarly, treatment of hippocampal neurons with AGEs significantly decreases synaptic density. Such detrimental effects are largely reversed by genetic RAGE depletion. Notably, brain slices from mice with neuronal RAGE deficiency or DN-RAGE are resistant to AGE-induced LTP deficit.
Taken together, these data show that neuronal RAGE functions as a signal transducer for AGE-induced synaptic dysfunction, thereby providing new insights into a mechanism by which the AGEs-RAGE-dependent signaling cascade contributes to synaptic injury via the p38 MAP kinase signal transduction pathway. Thus, RAGE blockade may be a target for development of interventions aimed at preventing the progression of cognitive decline in aging and age-related neurodegenerative diseases.