Cancer and Alzheimer’s disease inverse relationship: an age-associated diverging derailment of shared pathways

Lanni, Cristina; Masi, Mirco; Racchi, Marco; Govoni, Stefano

doi:10.1038/s41380-020-0760-2

Cited by 86 publications

(76 citation statements)

References 193 publications

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“…In the recent decade, there have been observations that patients with Alzheimer's disease have a lower incidence of cancer. Furthermore, patients with a history of cancer have a lower prevalence of AD, as was found in multiple studies [180,181]. This negative correlation occurs despite a surprising similarity in risk-factors for both diseases [182].…”

Section: What Happens With Lysosomes Damaged By Amyloidmentioning

confidence: 51%

Multiscale Analysis of the Amyloid Degradation Toxicity Hypothesis of Alzheimer’s Disease

Zaretsky¹,

Zaretskaia²

2020

Preprint

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Alzheimer's disease (AD) is the most common cause of dementia and affects millions of people around the world. Neuronal death in AD is initiated by the toxic action of oligomeric amyloid-β (Aβ) peptides. The formation of membrane channels by Aβ is a primary molecular action and does not require any other proteins. Channels are formed by short amyloid fragments faster and more frequently than by full-length peptides. The channel formation is dependent on an electrostatic interaction between a positively charged peptide and a negatively charged membrane. Negative membranes can be found in several locations of a cell – the inner leaflet of plasma membrane, mitochondria, and lysosomes, which all are well-known cellular targets in AD. Considering that the amyloid enters a cell by endocytosis and is exposed to lysosomal enzymes, we propose the amyloid degradation toxicity hypothesis. Endopeptidases degrade the endocytosed peptide. Produced fragments form membrane channels, which can transfer various ions (including protons) and even relatively large compounds. The neutralization of lysosomal content inactivates enzymes, which fails the whole system of recycling cellular content, including autophagy. The permeabilization of lysosomes could also lead to cell death through necrotic and apoptotic mechanisms. We discuss several mechanisms that describe how amyloid degradation products reach plasma and mitochondrial membranes, and form membrane channels. The pathogenesis of AD is discussed at various levels in a context of how the primary molecular mechanism of membrane channel formation could progress into the disease state. The discussion starts at the molecular level and extends to why the development of a disease takes years and is closely associated with aging. The proposed hypothesis offers an interpretation to several clinical observations such as the involvement of iron metabolism and an inverse association between developing Alzheimer's disease and cancer. Predictions about potential biomarkers and effectiveness of future treatments are discussed.

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Section: What Happens With Lysosomes Damaged By Amyloidmentioning

confidence: 51%

Multiscale Analysis of the Amyloid Degradation Toxicity Hypothesis of Alzheimer’s Disease

Zaretsky¹,

Zaretskaia²

2020

Preprint

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“…This anomaly allows distinguishing these cells from those of cognitively healthy subjects with the same age (Lanni et al, 2008). This is particularly intriguing in light of the consideration that appears to be an inverse correlation between cancer and AD due to shared biological mechanisms (Lanni et al, 2020).…”

Section: Discussionmentioning

confidence: 96%

The sTREM2 Concentrations in the Blood: A Marker of Neurodegeneration?

Ferri

Rossi

Geraci

et al. 2021

Front. Mol. Biosci.

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Microglia performs a variety of functions during brain development designed to maintain brain homeostasis. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in microglial cells modulating phagocytosis, cytokine production, cell proliferation, and cell survival. Interestingly, the levels of soluble TREM2 (the secreted ectodomain of TREM2, sTREM2) were higher in cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients than subjects without cognitive decline. It is noteworthy that, while CSF sTREM2 levels have been extensively studied, few studies have investigated sTREM2 in blood producing conflicting results. We aimed to investigate the levels of sTREM2 in CSF and blood from a cohort of well-characterized AD comparing the results to those obtained in patients suffering from idiopathic normal pressure hydrocephalus (iNPH), a potentially reversible cognitive impairment. Our findings underlined a significantly lower plasma sTREM2 concentration in AD patients compared to iNPH subjects [39.1 ng/mL (standard deviation (SD), 15.0) and 47.2 ng/mL (SD, 19.5), respectively; p = 0.01], whereas no difference was revealed between the two groups in the CSF sTREM2 levels. The adjusted regression analyses evidenced in AD patients an association between plasma and CSF sTREM2 levels [B = 0.411; 95% confidence interval (CI), 0.137–0.685, p = 0.004], as well as β-amyloid concentrations (B = 0.035; 95% CI, 0.007–0.063, p = 0.01) and an association between CSF sTREM2 and phospho-Tau concentrations (B = 0.248; 95% CI, 0.053–0.443; p = 0.01). No significant relation was found in iNPH patients. In conclusion, these differences in sTREM2 profiles between AD and iNPH reinforce the notion that this receptor has a role in neurodegeneration.

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“…The development of peptide based therapies involving incretins that can mitigate the degenerative processes in the brain is a major feat that shows promise. Controlling this major InsR and IGF1R, which are prominent and one of the most important albeit in age reversal [61,80] is yet to be achieved but picking up cues from diseases like cancer that elicits an alternate pathway [81], in terms of therapy could accelerate the process of developing therapies (Figure 3). The ability of growth factors to modulate cellular events such as ROS generation, energy utilization and others are remarkable and thus developing more sophisticated approaches using the knowledge thus gathered to invoke the right set of signals for slowing the cycle and early detection are important.…”

Section: Discussionmentioning

confidence: 99%

Possibilities of Combinatorial Therapy: Insulin Dysregulation and the Growth Hormone Perspective on Neurodegeneration

Sengupta¹,

Mukhopadhyay²

2021

Pharmacogenetics

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RTKs have been reported to be implicated in several neurodegenerative disorders and the roles of insulin receptor family have emerged as a key common pathway across diseases. Thus we focussed on the Insulin receptor family and discussed the irregulation from the growth hormone axis. The signaling, regulation and physiology of the production in liver and CNS has never been discussed in signaling perspectives and is extremely crucial for understanding the possibilities of IGF1 in neurodegeneration specifically. The commonalities across neurodegenerative diseases such as oxidative stress, mitochondrial dysfunction, and protein misfolding and insulin pathway anomalies have been elucidated and correlated with the insulin pathway. The crosstalk possibilities of the pathways, along with other regulatory modes for the development of combinatorial therapy have been discussed to visualize a common platform for neurodegenerative diseases including AD, PD, HD, ALS and FTD. Furthermore, the incretin based therapies that have gradually emerged as alternatives for insulin based therapy due to its inherent drawback of resistance has been briefly discussed.

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Cancer and Alzheimer’s disease inverse relationship: an age-associated diverging derailment of shared pathways

Cited by 86 publications

References 193 publications

Multiscale Analysis of the Amyloid Degradation Toxicity Hypothesis of Alzheimer’s Disease

Multiscale Analysis of the Amyloid Degradation Toxicity Hypothesis of Alzheimer’s Disease

The sTREM2 Concentrations in the Blood: A Marker of Neurodegeneration?

Possibilities of Combinatorial Therapy: Insulin Dysregulation and the Growth Hormone Perspective on Neurodegeneration

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