Investigating the Underlying Mechanisms between Aβ Plaque Accumulation and Neuronal Dysfunction in Alzheimer’s Disease Progression
Background. Alzheimer’s disease (AD) is a neurodegenerative disorder that results in memory loss, cognitive decline and changes in behavior and personality, and is the most common form of dementia for individuals over the age of 65 years old.6 There is no cure for Alzheimer’s disease; however, there are treatments and management strategies to delay progression of symptoms.6 One of the hallmarks of AD is the accumulation of Aβ plaques in the brain which is believed to be a primary cause for the dysfunction and death of hippocampal cholinergic neurons.6
Objective. The underlying mechanisms between Aβ plaque accumulation and neuronal dysfunction in AD progression remains unclear.6 Exploration into this area can offer crucial information for treatment research.
Search Methods. An online search in the PubMed database was conducted from 2017-2023 using keywords: “Aβ oligomers” “neuronal hyperactivity” and “neuronal dysfunction”.
Methods. A literature review consisting of several studies was conducted to further elucidate the mechanisms behind Aβ-plaque accumulation and neuronal dysfunction. Human-derived Aβ oligomers were injected into the hippocampus of mice, followed by using a genetic approach to delete Amyloid precursor protein (APP) to determine its effects on Aβ oligomers5. Researchers used electrophysiological recordings in hippocampal slices from AD transgenic mice and wild-type mice to measure neuronal hyperactivity using synthetic Aβ (1-40)S26C1. Researchers then explored the relevance of their findings to human disease by using a form of Aβ derived from AD brains1. Researchers also induced synaptic glutamate release by electrically stimulating afferent Shchaffer collateral axons in hippocampal slices to investigate the relationship between Aβ and glutamate transients2. Finally, researchers used a mouse model of AD to investigate the role of intracellular Calcium stores in neuronal hyperactivity by recording neuronal activity in the hippocampus in AD mouse models4.
Results. Aβ oligomers directly bound to synapses and disrupted synaptic activity, but hippocampal neurons were resistant to the effects of Aβ oligomers in APP-knockout mice5. Additionally, Aβ plaque accumulation induced a reversible increase in neuronal activity1; however, Aβ (1-40)S26C was ineffective in hippocampal slices in vitro, unless baseline neuronal activity was increased to the levels similar to in vivo conditions1. Aβ produced strong and reversible potentiation of glutamate transients and blocking glutamate reuptake induced neuronal hyperactivity in vivo similar to that observed with synthetic Aβ (1-40)S26C2 . Researchers also determined that endoplasmic reticulum calcium channels, RyR and IP3R, were upregulated in the hippocampus of AD mouse models3, and that Aβ oligomers increased the frequency and duration of these calcium channels in the hippocampal neurons4.
Conclusion. Aβ plaque accumulation requires APP to disrupt synaptic activity5, causes a vicious cycle of neuronal hyperactivity1 and contributes to calcium dysregulation3,4, all of which are implicated in the progression of AD. Targeting NMDAR’s, intracellular calcium levels, endoplasmic reticulum calcium channels and APP may provide potential therapeutic strategies for treating AD. Further research is needed to fully understand the underlying mechanisms between AD-induced calcium dysregulation and its role in memory loss and other cognitive impairments associated with AD pathogenesis.
- Zott B, Simon MM, Hong W, et al. A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science. 2019;365(6453):559-565. doi:10.1126/science.aay0198
- Bao Y, Yang X, Fu Y, et al. NMDAR-dependent somatic potentiation of synaptic inputs is correlated with β amyloid-mediated neuronal hyperactivity. Transl Neurodegener. 2021;10(1):34. doi: 10.1186/s40035-021-00260-3
- Guan PP, Cao LL, Wang P. Elevating the Levels of Calcium Ions Exacerbate Alzheimer’s Disease via Inducing the Production and Aggregation of β-Amyloid Protein and Phosphorylated Tau. Int J Mol Sci. 2021;22(11):5900. Published 2021 May 31. doi:10.3390/ijms22115900
- Lerdkrai C, Asavapanumas N, Brawek B, et al. Intracellular Ca2+ stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2018;115(6):1279-1288. doi:10.1073/pnas.1711961115.
- Wang Z, Jackson RJ, Hong W, et al. Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP. J Neurosci. 2017;37(50):11947-11966. doi:10.1523/JNEUROSCI.1773-17.2017
- Moreta MP, Burgos-Alonso N, Torrecilla M, Marco-Contelles J, Bruzos-Cidón C. Efficacy of Acetylcholinesterase Inhibitors on Cognitive Function in Alzheimer’s Disease. Review of Reviews. Biomedicines. 2021;9(11):1689. Published 2021 Nov 15. doi:10.3390/biomedicines9111689