The BACH1/Nrf2 Axis in Brain in Down Syndrome and Transition to Alzheimer Disease-Like Neuropathology and Dementia

Abstract

Down syndrome (DS) is the most common genetic cause of intellectual disability that is associated with an increased risk to develop early-onset Alzheimer-like dementia (AD). The brain neuropathological features include alteration of redox homeostasis, mitochondrial deficits, inflammation, accumulation of both amyloid beta-peptide oligomers and senile plaques, as well as aggregated hyperphosphorylated tau protein-containing neurofibrillary tangles, among others. It is worth mentioning that some of the triplicated genes encoded are likely to cause increased oxidative stress (OS) conditions that are also associated with reduced cellular responses. Published studies from our laboratories propose that increased oxidative damage occurs early in life in DS population and contributes to age-dependent neurodegeneration. This is the result of damaged, oxidized proteins that belong to degradative systems, antioxidant defense system, neuronal trafficking. and energy metabolism. This review focuses on a key element that regulates redox homeostasis, the transcription factor Nrf2, which is negatively regulated by BACH1, encoded on chromosome 21. The role of the Nrf2/BACH1 axis in DS is under investigation, and the effects of triplicated BACH1 on the transcriptional regulation of Nrf2 are still unknown. In this review, we discuss the physiological relevance of BACH1/Nrf2 signaling in the brain and how the dysfunction of this system affects the redox homeostasis in DS neurons and how this axis may contribute to the transition of DS into DS with AD neuropathology and dementia. Further, some of the evidence collected in AD regarding the potential contribution of BACH1 to neurodegeneration in DS are also discussed.

Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

“…An increasing number of studies have recently shown that increased OS is an early pathological characteristic of the DS brain and is involved in the onset and progression of AD due to the deregulation of gene/protein expression associated with HSA21 [ 71 , 72 , 73 , 74 ]. OS indicates a condition where pro-oxidant species overwhelm the cellular antioxidant defense system, by an increase of ROS production and/or by a decrease in the antioxidant response [ 17 ].…”

“…Noteworthy, the mechanisms responsible for the increase of OS levels in DS may be searched by mapping HSA21, where a number of genes, directly or indirectly, promote free radical production and alter the redox homeostasis of brain cells ( Figure 1 ). Among these, SOD1, APP, carbonyl reductase, and the transcription factor BTB and CNC homology 1 (Bach1) have been recognized as ROS inducers [ 73 , 74 ]. SOD1 catalyzes the dismutation of O 2 •− to O 2 and H 2 O 2 , the latter in turn is neutralized by catalase (CAT) and by glutathione peroxidase (GPX) to water [ 96 ].…”

“…Protein levels of both these enzymes were found to be increased in different brain regions of both DS and AD cases, indexing the cell response to increase carbonyl production [ 99 ]. BACH1 gene encode for a basic leucine zipper protein belonging to the cap’n’collar family that function as a transcription repressor [ 74 ]. In particular, Bach1 competes, in the nucleus, with Nrf2 for the binding to the antioxidant response elements (ARE).…”

Deciphering the links between psychological stress, depression, and neurocognitive decline in patients with Down syndrome

“…Similarly to neuroinflammation, increased free radical levels and oxidative stress disturb beta-amyloid clearance, which in turn induces cerebral amyloidosis ( Tönnies and Trushina, 2017 ). Neuronal oxidative stress also alters mitochondrial metabolism, enhances neuroinflammation, and increases apoptosis, causing neuronal loss and hyperphosphorylation of Tau proteins ( Butterfield and Boyd-Kimball, 2018 ; Perluigi et al, 2020 ).…”

“…Moreover, triplication of the S100B and APP genes upregulates the expression of IL-1B protein, which increases neuroinflammation ( Wilcock and Griffin, 2013 ). In terms of oxidative stress, patients with DS show higher oxidative stress levels because of alterations of the kynurenine metabolic pathway, decreased production of antioxidants, and triplication of the SOD1, RCAN1 and APP genes ( Gomez et al, 2020 ; Perluigi et al, 2020 ). Finally, patients with DS also show (i) increased tau hyperphosphorylation because of the triplication of the ETS2 and DYRK1A genes ( Gomez et al, 2020 ; Hartley et al, 2015 ), (ii) increased neuronal apoptosis caused by the coordinated action of SOD1, DYRK1A, and ETS2 ( Martínez-Cué and Rueda, 2020 ), (iii) increased mitochondrial dysfunction linked to the triplication of the S100B and SOD1 genes ( Dierssen et al, 2020 ), and (iv) altered endocytosis and synaptic trafficking because of triplication of the RCAN1 and SYNJ1 genes ( Gomez et al, 2020 ).…”