Activating transcription factor 4-dependent lactate dehydrogenase activation as a protective response to amyloid beta toxicity

Abstract

Accumulation of amyloid beta peptides is thought to initiate the pathogenesis of Alzheimer’s disease. However, the precise mechanisms mediating their neurotoxicity are unclear. Our microarray analyses show that, in Drosophila models of amyloid beta 42 toxicity, genes involved in the unfolded protein response and metabolic processes are upregulated in brain. Comparison with the brain transcriptome of early-stage Alzheimer’s patients revealed a common transcriptional signature, but with generally opposing directions of gene expression changes between flies and humans. Among these differentially regulated genes, lactate dehydrogenase (Ldh) was up-regulated by the greatest degree in amyloid beta 42 flies and the human orthologs (LDHA and LDHB) were down-regulated in patients. Functional analyses revealed that either over-expression or inhibition of Ldh by RNA interference (RNAi) slightly exacerbated climbing defects in both healthy and amyloid beta 42-induced Drosophila. This suggests that metabolic responses to lactate dehydrogenase must be finely-tuned, and that its observed upregulation following amyloid beta 42 production could potentially represent a compensatory protection to maintain pathway homeostasis in this model, with further manipulation leading to detrimental effects. The increased Ldh expression in amyloid beta 42 flies was regulated partially by unfolded protein response signalling, as ATF4 RNAi diminished the transcriptional response and enhanced amyloid beta 42-induced climbing phenotypes. Further functional studies are required to determine whether Ldh upregulation provides compensatory neuroprotection against amyloid beta 42-induced loss of activating transcription factor 4 activity and endoplasmatic reticulum stress. Our study thus reveals dysregulation of lactate dehydrogenase signalling in Drosophila models and patients with Alzheimer’s disease, which may lead to a detrimental loss of metabolic homeostasis. Importantly, we observed that down-regulation of ATF4-dependent endoplasmic reticulum-stress signalling in this context appears to prevent Ldh compensation and to exacerbate amyloid beta 42-dependent neuronal toxicity. Our findings therefore suggest caution in the use of therapeutic strategies focused on down-regulation of this pathway for treatment of Alzheimer’s disease, since its natural response to the toxic peptide may induce beneficial neuroprotective effects.

Opposite modulation of functional recovery following contusive spinal cord injury in mice with oligodendrocyte-selective deletions of Atf4 and Chop/Ddit3

“…Lipid synthesis is another critical component of myelin biogenesis and maintenance that may be positively regulated by ATF4 [52][53][54] . Moreover, ATF4 is a positive regulator of the lactate generating anerobic glycolysis, which is highly active in OLs to support axonal oxidative metabolism 55,56 , a mechanism which involves increased expression of the key lactate producing enzyme lactate dehydrogenase (LDH) 56 . Noteworthy, the Ldha transcript that encodes one of the two principal LDH isoforms in mammals shows a biphasic upregulation in SCI OL translatome that correlates with biphasic induction of ATF4/CHOP at dpi 2 and dpi 42 (4.86 and 3.84 fold naïve control, respectively, q<0.05).…”

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies

“…In a previous study we found that neuronal dLdh upregulation caused an increase in the number of brain vacuoles [51], indicative of neurodegeneration occurring in the fly brain with age [96]. Other studies in flies have recently shown that the toxic effect of amyloid beta, a peptide strongly implicated in neurodegeneration in Alzheimer’s disease, causes dLdh upregulation in part due to an Activating transcription factor 4 (ATF-4) dependent endoplasmic reticulum stress signalling unfolded protein response [52]. In accordance with our findings on neuronal dLdh impact on fly survival, the authors of this study also found that both upregulation and downregulation of neuronal dLdh caused an exacerbation of amyloid beta toxicity [52].…”

“…Other studies in flies have recently shown that the toxic effect of amyloid beta, a peptide strongly implicated in neurodegeneration in Alzheimer's disease, causes dLdh upregulation in part due to an Activating transcription factor 4 (ATF-4) dependent endoplasmic reticulum stress signalling unfolded protein response [52]. In accordance with our findings on neuronal dLdh impact on fly survival, the authors of this study also found that both upregulation and downregulation of neuronal dLdh caused an exacerbation of amyloid beta toxicity [52]. Furthermore, a recent finding demonstrated that ubiquitous disruption of the Ldhb gene within mice resulted in increased mitochondrial dysfunction, oxidative stress, apoptosis, and cognitive impairment [97].…”

“…Two recent findings suggest that D. melanogaster, in certain contexts, require glia to provide glucose or ketone bodies to fuel neurons, irrespective of lactate, and facilitate memory formation [48,49]. Moreover, findings by our laboratory and others have provided evidence that glia-neuron lactate shuttling in D. melanogaster impacts aging and neurodegeneration [36,51,52]. In addition, glia have been shown to contribute to age-related memory impairment [53,54].…”

The double-stranded RNA-dependent protein kinase inhibitor alleviates endoplasmic reticulum stress and alleviates sepsis-induced renal injury

“…ATF4 is a signaling molecule downstream of the Endoplasmic reticulum-resident kinase (PERK) pathway in the ER stress signaling pathway (Moulin et al, 2020). ATF4 plays an important role in ontogeny, cellular stress response, amino acid secretion, apoptosis and tumorigenesis (Niccoli et al, 2021;Chen et al, 2021a). As shown in Fig.…”