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Late-onset sporadic Alzheimer’s disease modeling using patient-derived cells: A review

ABSTRACT: Late-onset sporadic Alzheimer’s disease (LOAD) is the most common form of dementia. The disease is characterized by progressive loss of memory and behavioral changes followed by neurodegeneration of all cortical areas. While the contribution of genetic and environmental factors is important, advanced aging remains the most important disease risk factor. Because LOAD does not naturally occur in most know animal species, except humans, studies have traditionally relied on the use of transgenic mice modeling rare, early-onset genetic forms of Alzheimer’s disease. Hence, the development of more representative LOAD models through reprograming of patient-derived cells into neuronal, glial, and immune cells became a necessity to better understand the disease origin and pathophysiology. Herein, and focusing on neurons, we review current work in the field and compare results obtained with two different reprograming methods to generate patient-derived neuronal cells: the induced pluripotent stem cell and induced neuron technologies. We also evaluate if these models can faithfully mimic cellular and molecular pathologies observed in LOAD patient’s brains. Here, we show new ATAC-seq data that support that iPSC can faithfully model LOAD, with an increased number of peaks showing chromatin relaxation in LOAD neurons

ORGANISM(S): Homo sapiens

PROVIDER: GSE314553 | GEO | 2026/01/14

REPOSITORIES: GEO

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Project description:Neuronal overexcitability can disrupt synapse formation and strength and elicit synaptic changes which in turn give rise to neuronal hyperactivity, and eventually overall abnormal neural circuit processing. Such network disruption impairs neuronal function and survival, resulting in the onset of neurodegeneration and Alzheimer’s disease. Yet, the sequence of synaptic changes that result from sustained neuronal hyperactivity remain elusive. To address this, we adopted an optogenetic stimulation strategy to generate a model of long-lasting neuronal hyperactivity in hippocampal pyramidal neurons. We applied this to both wild-type mice and in the 5xFAD mice presenting mutations that confer susceptibility to develop Alzheimer’s disease in humans. We analyzed the proteome changes occurring after a month of daily chronic optogenetic stimulation which surprisingly revealed shared proteomic signatures between photoactivated wild-type and 5xFAD mice. Proteins involved in translation, protein transport, autophagy, and more importantly in the Alzheimer’s disease pathology were upregulated in wild-type mice. By contrast, optogenetic overdrive in the 5xFAD mice resulted in extensive downregulation of proteins participating in mRNA processing and phosphorylation. The footprint of protein change upon driving hyperactivity in the wild-type mice included downregulation of glutamatergic and GABAergic synapse proteins indicating potential disruption of synaptic transmission. Moreover, the target of rapamycin mTORC1 signaling pathway, involved in the onset of several neuropathological disorders, was hyperactive after the optogenetic activation in wild-type mice. In turn, these proteome and signalling changes in the hippocampus of wild-type mice resulted in spatial memory loss and notably augmented Αβ42 secretion. Altogether, these findings indicate that neuronal overexcitability and hyperactivity alone replicate the footprint of proteomic changes within the hippocampus seen in mice harboring Alzheimer’s disease-linked mutations. Thus, sustained neuronal hyperactivity may contribute to synaptic transmission disruption, memory deficits and the neurodegenerative process associated with Alzheimer’s disease.

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Late-onset sporadic Alzheimer’s disease modeling using patient-derived cells: A review

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