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Cell Biology

Alzheimer's Disease

Worldwide, dementia is considered the seventh leading cause of death and has been classified as a global public health priority by the World Health Organization (WHO) [1]. The outlook for the future appears particularly alarming due to demographic change. In Germany alone, 2.8 million people are projected to be living with dementia by 2050, representing a 65% increase compared to 2019 [2]. Dementia presents in many forms, with Alzheimer's disease being the most common, accounting for 60–70% of all cases [1]. The disease has a significant impact on daily life—not only for those affected but also for family members and caregivers [3,4]. Although treatments exist to alleviate symptoms, there is currently no cure [5]. Due to the immense social impact of the disease, continued research into potential therapeutic approaches is essential. Alzheimer's disease is triggered by a combination of lifestyle and environmental factors, as well as genetic predisposition [6]. While the disease can be inherited, the associated genes also serve as potential targets for therapeutic intervention [7, 8]. We are investigating Alzheimer’s disease in relation to the 'Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells' (NF-κB). The activation of this transcription factor is crucial for neuronal protection; however, in many affected individuals, TNFα-mediated NF-κB activation is impaired due to germline mutations. The genetic context may also aid in the earlier identification of Alzheimer’s disease, allowing for timely initiation of therapeutic strategies.

Overview of TNFR1-mediated activation of NF-κB dependent on linear ubiquitin. Membrane-bound TNF could be released by proteolytic cleavage mediated by ADAM17, resulting in intracellular signaling dependent on linear ubiquitin (small blue pearls). Activation of trimeric IKK complex could trigger nuclear localization of REL or RELA, which are controlled by feedback loops with IκBα or IκBε (modified from Sasaki et al., 2023 [53]). Alternatively, when ubiquitination of RIPK 1 is inhibited, interaction with FADD occurs, leading to activation of CASPASE-8-mediated cell death. In contrast, if CASPASE-8 is inhibited, RIPK3 interacts with MLKL, leading to necroptosis [9].

References

[1] World Health Organization: Dementia. Online verfügbar unter https://www.who.int/news-room/fact-sheets/detail/dementia#:~:text=Worldwide%2C%20around%2055%20million%20people,and%20139%20million%20in%202050., zuletzt geprüft am 26.10.2022.

[2] Nichols et al.: Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. The Lancet Public Health. 2022.

[3] Lane et al.: Alzheimer's disease. European journal of neurology. 2018.

[4] Athanasiadou et al.: Care of Patients with Alzheimer's Disease. Advances in experimental medicine and biology. 2021

[5] Breijyeh and Karaman: Comprehensive Review on Alzheimer's Disease: Causes and Treatment. Molecules. 2020.

[6] Sun et al.: The Pivotal Role of NF-kB in the Pathogenesis and Therapeutics of Alzheimer's Disease. International journal of molecular sciences. 2022.

[7] Bellenguez et al.: New insights into the genetic etiology of Alzheimer's disease and related dementias. Nature genetics. 2022

[8] Gatz et al.: Role of genes and environments for explaining Alzheimer disease. Archives of general psychiatry. 2006

[9] Kaltschmidt et al.: NF-κB in Alzheimer’s Disease: Friend or Foe? Opposite Functions in Neurons and Glial Cells. Int. J. Mol. Sci. 2024.

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