Friend or Foe? Defining the Role of Glutamate in Aging and Alzheimer’s Disease

Abstract

Aging is a naturally occurring decline of physiological processes and biological pathways that affects both the structural and functional integrity of the body and brain. These physiological changes reduce motor skills, executive function, memory recall, and processing speeds. Aging is also a major risk factor for multiple neurodegenerative disorders including Alzheimer’s disease (AD). Identifying a biomarker, or biomarkers, that signals the transition from physiological to pathological aging would aid in earlier therapeutic options or interventional strategies. Considering the importance of glutamate signaling in synaptic plasticity, motor movement, and cognition, this neurotransmitter serves as a juncture between cognitive health and disease. This article discusses glutamatergic signaling during physiological aging and the pathological changes observed in AD patients. Findings from studies in mouse models of successful aging and AD are reviewed and provide a biological context for this transition. Finally, current techniques to monitor brain glutamate are highlighted. These techniques may aid in elucidating time-point specific therapeutic windows to modify disease outcome.

The Hippocampal Glutamate/GABA System is Affected by Aging but not by an Alzheimer’s Disease-Like Pathology in Rats

“…In many species, reduced glutamatergic signaling can be interpreted as a biologically conserved mechanism of aging similar to sarcopenia or osteoporosis (Cox et al 2022). Accordingly, this decline and in general, synaptic plasticity damage should accelerate with premature aging, including during AD progression.…”

Age, Education Years, and Biochemical Factors Are Associated with Selective Neuronal Changes in the Elderly Hippocampus

“…The other five studies evaluated individuals with a maximum of 88 years. In a review of the recent literature, it was acknowledged that although there is a general consensus for an age-related decline in glutamatergic signaling, little information regarding the oldest-old is available [ 33 ].…”

“…There is also in vivo evidence that neurons regionally close to Aβ plaques develop a hyperactive phenotype while neurons farther away appear to be silenced [ 71 ]. Notwithstanding, Aβ plaques seem to downregulate VGLUT1 expression in patients at late stages of AD [ 33 , 72 , 73 ]. In this context, our results suggest that non-demented subjects are more likely to reach old age rather and present a positive association between Aβ and VGLUT1 than the downregulation observed in advanced AD patients.…”

“…In humans, a considerable body of evidence points to an age-related reduction in glutamate levels [ 31 , 32 ]. However, there is little data regarding VGLUT changes, especially in nonagenarians and centenarians [ 33 ].…”

Neuroendocrine Control of Hyperglutamatergic States in Brain Pathologies: the Effects of Glucocorticoids

“…The universal interneuronal interface, synapse, is a key element of brain plasticity. Glutamate is the most common neurotransmitter in the CNS, with its receptors being present on more than 90% of neurons and 40% of synapses [13]. Currently, more than 20 glutamate receptors (ionotropic that represent an ion channel, and metabotropic, sig nal transduction through which is mediated by secondary messengers) have been identified in the CNS, with each individual receptor having several subtypes.…”