optimized-automated-analysis-live-neuronal-mitochondria-homeostasis

Optimized Automated Analysis of Live Neuronal Mitochondria Homeostasis Modulation by Isoform-Specific Retinoic Acid Receptors

The complex mitochondrial network makes it very challenging to segment, follow, and analyze live cells. MATLAB tools allow the analysis of mitochondria in ...

University of Aveiro

Protein aggregation is normally associated with amyloidosis, namely motor neurone, Alzheimer's, Parkinson's or prion diseases. However, recent results have unveiled a concept of gradual increase of protein aggregation associated with the ageing process, apparently not necessarily associated with pathological conditions. Given that protein aggregation is sufficient to activate stress-response and inflammation, impairing protein synthesis and quality control mechanisms, the former is assumed to negatively affect cellular metabolism and behaviour. In this review the state of the art in protein aggregation research is discussed, namely the relationship between pathology and proteostasis. The role of pathology and ageing in overriding protein quality-control mechanisms, and consequently, the effect of these faulty cellular processes on pathological and healthy ageing, are also addressed.

Unravelling protein aggregation as an ageing related process or a neuropathological response.

Lacking conventional lymphatic system, the central nervous system requires alternative clearance systems, such as the glymphatic system, which promotes clearance of interstitial solutes. Aquaporin-4 water channels (AQP4) are an integral part of this system and related to neuropathologies, such as Alzheimer's disease (AD). The clearance of Alzheimer's associated proteins amyloid β and tau is diminished by glymphatic system impairment, due to lack of AQP4. Even though AQP4 mislocalisation (which affects its activity) is a phenotype of AD, it remains a controversial topic, as it is still unclear if it is a phenotype-promoting factor or a consequence of this pathology. This review provides important and updated knowledge about glymphatic system, AQP4 itself, and their link with Alzheimer's disease. Finally, AQP4 as a therapeutic target is proposed to ameliorate Alzheimer's Disease and other neuropathologies AQP4-related.

Glymphatic system, AQP4, and their implications in Alzheimer's disease.

Mitochondria are associated with various cellular activities critical to homeostasis, particularly in the nervous system. The plastic architecture of the mitochondrial network and its dynamic structure play crucial roles in ensuring that varying energetic demands are rapidly met to maintain neuronal and axonal energy homeostasis. Recent evidence associates aging and neurodegeneration with anomalous neuronal metabolism as age-dependent alterations of neuronal metabolism are now believed to occur prior to neurodegeneration. The brain has a high energy demand, which makes it particularly sensitive to mitochondrial dysfunction. Distinct cellular events causing oxidative stress or disruption of metabolism and mitochondrial homeostasis can trigger a neuropathology. This review explores the bioenergetic hypothesis for the neurodegenerative pathomechanisms, discussing factors leading to age-related brain hypometabolism and its contribution to cognitive decline. Recent research on the mitochondrial network in healthy nervous system cells, its response to stress, and how it is affected by pathology, as well as current contributions to novel therapeutic approaches will be highlighted.

Mitochondria, energy, and metabolism in neuronal health and disease.

Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the accumulation of the β-amyloid peptide (Aβ) in the brain, along with profound alterations in phosphorylation-related events and regulatory pathways. The production of the neurotoxic Aβ peptide via amyloid precursor protein (APP) proteolysis is a crucial step in AD development. APP is highly expressed in the brain and is complexly metabolized by a series of sequential secretases, commonly denoted the α-, β-, and γ-cleavages. The toxicity of resulting fragments is a direct consequence of the first cleaving event. β-secretase (BACE1) induces amyloidogenic cleavages, while α-secretases (ADAM10 and ADAM17) result in less pathological peptides. Hence this first cleavage event is a prime therapeutic target for preventing or reverting initial biochemical events involved in AD. The subsequent cleavage by γ-secretase has a reduced impact on Aβ formation but affects the peptides' aggregating capacity. An array of therapeutic strategies are being explored, among them targeting Retinoic Acid (RA) signalling, which has long been associated with neuronal health. Additionally, several studies have described altered RA levels in AD patients, reinforcing RA Receptor (RAR) signalling as a promising therapeutic strategy. In this review we provide a holistic approach focussing on the effects of isoform-specific RAR modulation with respect to APP secretases and discuss its advantages and drawbacks in subcellular AD related events.

Revisiting APP secretases: an overview on the holistic effects of retinoic acid receptor stimulation in APP processing.

In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors (such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer's disease and Parkinson's disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.

Novel therapeutic strategies targeting mitochondria as a gateway in neurodegeneration.

The plastic architecture of the mitochondrial network and its dynamic structure play crucial roles ensuring that varying energetic demands are rapidly met. Given the brain's high energy demand, mitochondria play a particularly critical role in neuronal and axonal energy homeostasis. With ageing physiological properties of the organism deteriorate, and are associated with loss of cellular homeostasis, accumulation of dysfunctional organelles and damaged macromolecules. Thus, mitochondrial loss of efficiency is likely to be both a cause and a consequence of ageing. Additionally distinct cellular events can contribute to oxidative stress, disruption of metabolism and mitochondria homeostasis, resulting in neuropathology. However, although the correlation between ageing and mitochondria disfunction is well established, the response to oxidative stress, particularly proteostasis, remains to be fully elucidated. The work here described explores the degradation of mitochondria oxidative stress-response mechanisms with ageing in human cells, addressing the physiological effects on proteostasis, focused on its role in differentiating between healthy and pathological ageing. Increased protein aggregation appears to be tightly related to impairment of ageing mitochondria response to oxidative stress, and antioxidative agents are shown to have a progressive protective effect with age; cells from old individuals show higher susceptibility to oxidative stress, in terms of protein aggregation, cell viability, or mitochondria homeostasis. These results support the antioxidant properties of flavonoids as a good therapeutic strategy for age-related diseases. Given their protective effect, this family of compounds can be of strategic therapeutic value for protein-aggregation related diseases.

Mitochondria dysfunction and impaired response to oxidative stress promotes proteostasis disruption in aged human cells.

Ageing is characterized by the progressive loss of cellular homeostasis, leading to an overall decline of the organism's fitness. In the brain, ageing is highly associated with cognitive decline and neurodegenerative diseases. With the rise in life expectancy, characterizing the brain ageing process becomes fundamental for developing therapeutic interventions against the increased incidence of age-related neurodegenerative diseases and to aim for an increase in human life span and, more importantly, health span. In this review, we start by introducing the molecular/cellular hallmarks associated with brain ageing and their impact on brain cell populations. Subsequently, we assess emerging evidence on how systemic ageing translates into brain ageing. Finally, we revisit the mainstream and the novel rejuvenating strategies, discussing the most successful ones in delaying brain ageing and related diseases.

Article	Year
Unravelling protein aggregation as an ageing related process or a neuropathological response. Ageing research reviews\| PubMed ID: 30763619	2019
Glymphatic system, AQP4, and their implications in Alzheimer's disease. Neurological research and practice\| PubMed ID: 33499944	2021
Mitochondria, energy, and metabolism in neuronal health and disease. FEBS letters\| PubMed ID: 35088449	2022
Revisiting APP secretases: an overview on the holistic effects of retinoic acid receptor stimulation in APP processing. Cellular and molecular life sciences : CMLS\| PubMed ID: 35089425	2022
Novel therapeutic strategies targeting mitochondria as a gateway in neurodegeneration. Neural regeneration research\| PubMed ID: 36254979	2023
Mitochondria dysfunction and impaired response to oxidative stress promotes proteostasis disruption in aged human cells. Mitochondrion\| PubMed ID: 36273801	2023
Ageing in the brain: mechanisms and rejuvenating strategies. Cellular and molecular life sciences : CMLS\| PubMed ID: 37354261	2023

Diogo Trigo

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