Upregulation of Cisd2 attenuates Alzheimer's‐related neuronal loss in mice

Abstract

CDGSH iron–sulfur domain‐containing protein 2 (Cisd2), a protein that declines in an age‐dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid β (Aβ) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two‐fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aβ‐mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild‐type mice. These findings highlight Cisd2‐based therapies as a potential disease‐modifying strategy for AD. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Cisd2: a promising new target in Alzheimer's disease†

“…In a recent issue of The Journal of Pathology , Chen et al describe the role of Cisd2 in a validated transgenic mouse model of AD, showing how Cisd2 overexpression may be able to protect mitochondria from Aβ load [3]. Below, we summarise the key results of this paper, together with previous breakthroughs on Cisd2 functions.…”

“…In their most recent article in this Journal, Chen et al cleverly made another important step forward in disentangling the importance of Cisd2 for proper neuronal function, by crossing their Cisd2-overexpressing mice with the APP/PS1 mouse model of AD [3]. One of the leading theories of degeneration in AD is the Ca 2+ hypothesis, which proposes that alterations in intracellular Ca 2+ in neurons is a central mechanism connecting amyloid metabolism to neuronal cell death, linking alterations to Ca 2+ homeostasis with mitochondrial dysfunction, metabolic and oxidative stress, impaired lysosomal function, and deficits in autophagic mechanisms.…”

“…A Nobili, P Krashia et al age-associated damage, the crossing of an AD mouse with the Cisd2-overexpressing mouse should ameliorate the AD phenotype and protect neurons from cell death [3]. Indeed, the authors demonstrated that Cisd2 levels in the hippocampus and cortex were nearly double in AD/Cisd2 mice compared with either AD or wild-type mice, and this overexpression significantly increased the lifespan of female AD/Cisd2 mice (while it had no effect in males that anyway showed a normal lifespan).…”

The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases

“…When CISD2 is overexpressed in AD mice, reduced neuron loss, β-amyloid-induced mitochondrial dysfunction, and decreased immunofluorescence of Iba1 (ionized calcium-binding adapter molecule 1) and GFAP have been reported in the hippocampus [ 84 ].…”

CISD2 Attenuates Inflammation and Regulates Microglia Polarization in EOC Microglial Cells—As a Potential Therapeutic Target for Neurodegenerative Dementia

“…Moreover, CISD2 attenuates the excitotoxic Ca 2+ surge at the endoplasmic reticulum by binding to BCL2 and the inositol 1,4,5-triphosphate receptor (Chang et al, 2012 ). Furthermore, overexpression of CISD2 has been demonstrated to attenuate neuronal loss and β-amyloid-induced mitochondrial dysfunction in the AD mouse model (Chen et al, 2020 ). Thus, CISD2 holds promise as a potential therapeutic target for neurodegenerative dementia.…”