Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
This week, we would like to share several latest articles on Pathogenesis of Neurodegenerative Diseases.
Title: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases
Authors: Hasan Turkez, Ozlem Altay, Serkan Yildirim, Xiangyu Li, Hong Yang, Cemil Bayram, Ismail Bolat, Sena Oner, Ozlem Ozdemir Tozlu, Mehmet Enes Arslan, Muhammad Arif, Burak Yulug, Lutfu Hanoglu, Seyda Cankaya, Simon Lam, Halil Aziz Velioglu, Ebru Coskun, Ezgi Idil, Rahim Nogaylar, Rahim Nogaylar, Ahmet Ozsimsek, Adil Mardinoglu
Type: Research Article
Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism.
We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation.
Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats.
Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.
Access this article: https://doi.org/10.1016/j.lfs.2022.121325
Title: Dipeptidyl peptidase 4(DPP4) inhibitors stride up the management of Parkinson's disease
Authors: Maanvi, Shilpa Kumari, Rahul Deshmukh
Parkinson's disease (PD) is the 2nd most common age-related hypokinetic disorder, characterized by dopaminergic degeneration and movement abnormalities. Dopaminergic degeneration in the basal ganglia is primarily seen in PD patients. The therapeutic strategies currently under investigation are to rescue dopaminergic degeneration and promote neuronal regeneration, which could halt disease progression. On the other hand, the therapeutic efficacy of existing drugs used in other disorders has been repurposed in neurodegenerative pathologies. DPP4 inhibitors widely used in treating diabetes have been considered viable target sites and are being tested for efficacy in neurodegenerative pathologies. DPP4 inhibitors have been reported to rescue neuronal degeneration and improve motor functions in various preclinical and clinical PD studies. The current review is focused on the neuroprotective potential, molecular mechanisms and therapeutic potential of DPP4 inhibitors in PD pathology.
Access this article: https://doi.org/10.1016/j.ejphar.2022.175426
Title: Brain regions show different metabolic and protein arginine methylation phenotypes in frontotemporal dementias and Alzheimer's disease
Authors: Fangrong Zhang, Anastasia Rakhimbekova, Tammaryn Lashley, Tobias Madl
Type: Research Article
Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease with multiple histopathological subtypes. FTD patients share similar symptoms with Alzheimer’s disease (AD). Hence, FTD patients are commonly misdiagnosed as AD, despite the consensus clinical diagnostic criteria. It is therefore of great clinical need to identify a biomarker that can distinguish FTD from AD and control individuals, and potentially further differentiate between FTD pathological subtypes. We conducted a metabolomic analysis on post-mortem human brain tissue from three regions: cerebellum, frontal cortex and occipital cortex from control, FTLD-TDP type A, type A-C9, type C and AD. Our results indicate that the brain subdivisions responsible for different functions show different metabolic patterns. We further explored the region-specific metabolic characteristics of different FTD subtypes and AD patients. Different FTD subtypes and AD share similar metabolic phenotypes in the cerebellum, but AD exhibited distinct metabolic patterns in the frontal and occipital regions compared to FTD. The identified brain region-specific metabolite biomarkers could provide a tool for distinguishing different FTD subtypes and AD and provide the first insights into the metabolic changes of FTLD-TDP type A, type A-C9, type C and AD in different regions of the brain. The importance of protein arginine methylation in neurodegenerative disease has come to light, so we investigated whether the arginine methylation level contributes to disease pathogenesis. Our findings provide new insights into the relationship between arginine methylation and metabolic changes in FTD subtypes and AD that could be further explored, to study the molecular mechanism of pathogenesis.
Access this article: https://doi.org/10.1016/j.pneurobio.2022.102400
Title: Insulin resistance in Alzheimer’s disease: The genetics and metabolomics links
Authors: Arwa M. Amin, Hamza Mostafa, Hani M.J. Khojah
Alzheimer's disease (AD) is a neurodegenerative disease with significant socioeconomic burden worldwide. Although genetics and environmental factors play a role, AD is highly associated with insulin resistance (IR) disorders such as metabolic syndrome (MS), obesity, and type two diabetes mellitus (T2DM). These findings highlight a shared pathogenesis. The use of metabolomics as a downstream systems’ biology (omics) approach can help to identify these shared metabolic traits and assist in the early identification of at-risk groups and potentially guide therapy. Targeting the shared AD-IR metabolic trait with lifestyle interventions and pharmacological treatments may offer promising AD therapeutic approach. In this narrative review, we reviewed the literature on the AD-IR pathogenic link, the shared genetics and metabolomics biomarkers between AD and IR disorders, as well as the lifestyle interventions and pharmacological treatments which target this pathogenic link.
Access this article: https://doi.org/10.1016/j.cca.2022.12.016
Title: Premotor, nonmotor and motor symptoms of Parkinson's Disease: A new clinical state of the art
Authors: Ana Beatriz Ramalho Leite Silva, Roger Wilson Gonçalves de Oliveira, Guilherme Pinheiro Diógenes, Marina Feitosa de Castro Aguiar, Camilla Costa Sallem, Micael Porto Portela Lima, Luciano Barroso de Albuquerque Filho, Sara Diógenes Peixoto de Medeiros, Lucas Lopes Penido de Mendonça, Paulo Cesar de Santiago Filho, Diogo Pasquali Nones, Pamella Mendes Martiniano da Silva Cardoso, Michelle Zonkowski Ribas, Stéfani Lara Galvão, Gabriel Felipe Gomes, Amanda Rebouças Bezerra de Menezes, Nayla Lima dos Santos, Victor Monteiro Mororó, Fairane Sousa Duarte, Júlio César Claudino dos Santos
Parkinson's Disease (PD) is a neurodegenerative disorder that affects dopaminergic neurons in the mesencephalic substantia nigra, causing a progressive clinical course characterized by pre-motor, non-motor and motor symptoms, which negatively impact the quality of life of patients and cause high health care costs. Therefore, the present study aims to discuss the clinical manifestations of PD and to make a correlation with the gut–brain (GB) axis, approaching epidemiology and therapeutic perspectives, to better understand its clinical progression and identify symptoms early. A literature review was performed regarding the association between clinical progression, the gut–brain axis, epidemiology, and therapeutic perspectives, in addition to detailing pre-motor, non-motor symptoms (neuropsychiatric, cognitive, autonomic, sleep disorders, sensory abnormalities) and cardinal motor symptoms. Therefore, this article addresses a topic of extreme relevance, since the previously mentioned clinical manifestations (pre-motor and non-motor) can often act as prodromal markers for the early diagnosis of PD and may precede it by up to 20 years.
Access this article: https://doi.org/10.1016/j.arr.2022.101834