Is Vulnerability of the Dentate Gyrus to Aging and Amyloid-β_1–42 Neurotoxicity Linked with Modified Extracellular Zn²⁺ Dynamics?

Abstract

The basal levels of extracellular Zn 2 are in the range of low nanomolar concentrations in the hippocampus and perhaps increase age-dependently. Extracellular Zn 2 dynamics is critical for cognitive activity and excess influx of extracellular Zn 2 into hippocampal neurons is a known cause of cognitive decline. The dentate gyrus is vulnerable to aging in the hippocampus and affected in the early stage of Alzheimer's disease (AD). The reasons remain unclear. Neurogenesis-related apoptosis may induce non-specific neuronal depolarization by efflux of intracellular K in the dentate gyrus and be markedly increased along with aging. Extracellular Zn 2 influx into dentate granule cells via high K -induced perforant pathway excitation leads to cognitive decline. Modified extracellular Zn 2 dynamics in the dentate gyrus of aged rats is linked with vulnerability to cognitive decline. Amyloid-β 1-42 (Aβ 1-42 ) is a causative candidate for AD pathogenesis. When Aβ 1-42 concentration reaches picomolar in the extracellular compartment in the dentate gyrus, Zn-Aβ 1-42 is formed in the extracellular compartment and rapidly taken up into dentate granule cells, followed by Aβ 1-42 -induced cognitive decline that is due to Zn 2 released from Aβ 1-42 , suggesting that dentate granule cells are sensitive to extracellular Zn 2 -dependent Aβ 1-42 toxicity. This paper deals with proposed vulnerability of the dentate gyrus to aging and Aβ 1-42 neurotoxicity.

In vivo synaptic activity-independent co-uptakes of amyloid β1–42 and Zn2+ into dentate granule cells in the normal brain

“…We propose a hypothesis that Zn-Aβ oligomers formed in the extracellular compartment are directly incorporated into neuronal membranes and form Zn 2+ -permeable ion channels. Because extracellular Zn 2+ is age-relatedly increased in the rat hippocampus 40 , Zn-Aβ 1–42 oligomers are more readily produced in the extracellular compartment of the aged hippocampus, followed by vulnerability to Zn-Aβ 1–42 oligomers in aging 16,41 . Therefore, controlling intracellular Zn 2+ dysregulation may be an effective strategy for overcoming AD pathogenesis.…”

Age-Dependent Remarkable Regenerative Potential of the Dentate Gyrus Provided by Intrinsic Stem Cells

“…The exceptional vulnerability of the DG is also evidenced in other human pathologies, such as frontotemporal lobe degeneration, Alzheimer's disease, and adrenal insufficiency (Maehlen and Torvik, 1990;Armstrong et al, 2012;Collins et al, 2012;Kovacs et al, 2013;Takeda and Tamano, 2018) and in rodent models of these and other pathologies that are often associated with enhanced neurogenesis (Spanswick et al, 2007(Spanswick et al, , 2011Watanabe et al, 2016;Choi et al, 2017;Tu et al, 2018;F. Wang et al, 2018).…”

Prostaglandin D2 pathway in a transgenic rat model of Alzheimer’s disease: therapeutic potential of timapiprant a DP2 antagonist

“…Interestingly, we found that neuronal loss at 11 months of age was specific to the DG and its subregions GCL and CA3c in the hippocampal tissue. The DG is known to be vulnerable to aging and to be affected in the early stages of AD [62]. In fact it is reported that in AD the GCL of the DG has impaired firing [49].…”