What cellular and molecular mechanisms drive early neurodegeneration and vulnerability in the medial temporal cortex during Alzheimer’s disease?
In many neurodegenerative diseases, including Alzheimer’s disease (AD), neuropathogenesis is marked by the selective vulnerability of certain neuronal populations and a predictable spread of pathology. The entorhinal cortex (EC), the main source of cortical sensory inputs to the hippocampus, is especially prone to early synaptic disruption and neuronal loss in AD. This loss correlates with increased Aβ oligomers in cerebrospinal fluid, yet the underlying mechanisms remain underexplored. We have shown that soluble Aβ1-42 oligomers, the most neurotoxic form, initiate early synaptic alterations through presynaptic Ca2+ conductance and vesicular glutamate trafficking, also affecting mitochondrial signaling in the EC. Additionally, Aβ-induced synaptic dysfunction in the EC relies on the co-activation of both GLUN2A and GLUN2B NMDA receptor subunits (see insert figures). (Olajide et.al., 2022 – Front. Aging Neurosci.; Olajide et al., 2021 – Neurobiol. Aging; Olajide et al., 2021 – Bio Open; Olajide et.al., 2021 – J Mol Neurosci.)
Current approach – deciphering the mechanisms underlying the vulnerability to synaptic degeneration.
Synaptic failure, rather than cell death, primarily correlates with early memory deficits in AD. However, the mechanisms driving early synaptic degeneration in the entorhinal cortex remain unclear. Through in vivo and ex vivo experiments, we aim to characterize the timing of cellular and molecular changes in vulnerable neurons and identify mechanisms contributing to synaptic loss and behavioural deficits. Ongoing studies will also evaluate the neuroprotective potential of antioxidant compounds, including our previously developed formulations.
What sex-driven modifiers underly early entorhinal cortex degeneration in Alzheimer’s disease?
Approximately two-thirds of AD patients are women, with estrogen reduction being a key risk factor. While age, hormones, inflammation, genetics, and frailty may all contribute to women’s higher AD incidence, the exact sex-related factors remain unclear. Few studies have examined the molecular mechanisms underlying this vulnerability in the EC. Our recent research demonstrates that estrogen loss from ovariectomy impairs cholinergic function, disrupts mitochondrial signaling, and causes synaptic damage in the EC. Reduced estrogen levels also impair mitochondrial respiration, likely increasing oxidative stress and degrading synaptic proteins essential for entorhinal-hippocampal cognition, thus heightening EC susceptibility to AD (see figure). (Olajide et al. 2024 – Neuroscience; Batallán Burrowes et al., 2022 – PLoS One)
Current approach – the role of estrogen loss on synaptic functions and implications for AD pathogenesis.
The cellular and molecular mechanisms driving higher AD incidence in women remain unclear. Our group is investigating the comorbid effects of AD risk factors—environmental stimulants—in ovariectomized rats with or without estrogen supplementation, along with targeted pharmacological testing.
Does developmental exposure to environmental factors promote vulnerability and susceptibility to neurodegeneration and behavioural dysfunction later in life
Human exposure to drug chemicals and environmental neurotoxicants during gestation can impact neurophysiological health later in life. Our research demonstrates that exposure to environmental toxicants at critical developmental stages disrupts the redox balance, induces oxidative stress and neuroinflammation, and ultimately dysregulates synaptic plasticity, cholinergic functions, and behaviour in adulthood. (Bamisi et al., 2024 – Neurotoxicol Teratol.; Olajide et al., 2021 – Neurotoxicol Teratol.)
Current approach – the neurodevelopmental impact of exposure to chemotoxins and selective vulnerability in AD. We are now using a series of experiments to investigate how acute and chronic in-utero exposure to common and rare environmental neurotoxicants can increase selective vulnerability and alter the cellular and molecular expression of synaptic elements in key brain regions of mice. This line of research is expected to identify how this phenomenon contributes to mechanisms driving susceptibility to AD-related pathologic changes, particularly early neuronal and synaptic dysfunction within the medial temporal lobe.