Diapositiva 1

[Audio] Neurodegenerative diseases are a group of conditions characterized by progressive degeneration of neurons in various parts of the brain, leading to impaired cognitive function, such as memory and language loss. This degeneration can result in dementia, a condition where an individual experiences significant difficulties in performing everyday tasks due to memory loss, confusion with time or location, slurred speech, and mood changes..

[Audio] A degenerative disease is a condition where the affected body part deteriorates over time, leading to a worsening condition due to the decline of its function and structure. This can occur in various parts of the body, including the brain, which can lead to neurodegenerative diseases such as Alzheimer's. In this case, the brain undergoes significant changes, resulting in impaired cognitive function and memory loss..

[Audio] In many neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's, cellular signaling pathways play a crucial role in the progression of the disease. Oxidative stress, which can lead to the accumulation of damaged proteins and the activation of pro-inflammatory responses, is one key factor contributing to this process. As we age, our cells become less efficient at removing these damaged proteins, allowing them to accumulate and contribute to the development of neurodegenerative diseases. Additionally, aging itself can also disrupt cellular signaling pathways, leading to changes in gene expression and protein synthesis that promote the onset of these diseases..

Examples. Diabetes Cardiovascular diseases Stroke Sexual dysfunction Degenerative diseases Obesity Neurodegenerative diseases Cancer Arthritis Respiratory diseases Platelet Aggregation and Thrombosis.

[Audio] Neurodegenerative diseases are a group of conditions that cause progressive damage to the neurons in the central nervous system. The diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Batten disease. All of these disorders have unique features, but they share a common characteristic - the gradual degradation of neural tissue, which leads to impaired cognitive, motor, and sensory functions..

[Audio] The damage caused by Alzheimer's disease results in dementia, which is a broad term encompassing the loss of memory and other cognitive abilities severe enough to hinder daily activities. Notably, Alzheimer's disease is responsible for 60-80 percent of all dementia cases, whereas Lewy Body dementia, vascular dementia, and mixed dementia account for smaller proportions. The manifestations of dementia include memory loss, visual impairment, disorientation with respect to time or place, slurred speech, difficulties with task completion, and mood fluctuations..

[Audio] The degenerative process in neurodegenerative diseases results in the loss of cognitive function, including memory and language. This decline is evident in Alzheimer's disease, where amyloid plaques accumulate in the brain, causing damage to neurons and ultimately leading to dementia. On the other hand, Huntington's disease is caused by an expansion of CAG repeats in the Huntingtin gene, which leads to the degeneration of neural cells and ultimately, fatal consequences..

[Audio] Huntington's Disease is an inherited disorder caused by a mutation in the Huntingtin gene on chromosome 4. This genetic defect leads to the progressive degradation of nerve cells in the brain, resulting in cognitive, motor, and psychiatric symptoms. The disease typically begins in adulthood, around age 30, and worsens over time, ultimately leading to premature death..

[Audio] ALS is a devastating disease that affects the motor neurons in the spinal cord and brain. As these nerve cells degenerate, people with ALS gradually lose control over their muscles, leading to paralysis and ultimately, death. The most common symptoms of ALS include muscle weakness, muscle cramps and spasms, difficulty speaking and swallowing, and trouble breathing. In addition, many individuals with ALS experience anxiety, depression, and cognitive impairment..

[Audio] The immune system plays a crucial role in attacking the protective sheath of nerve cells, known as myelin, which leads to permanent damage of neurons. This degenerative disease affects the brain and spinal cord, causing significant harm to those who suffer from it..

[Audio] The Batten disease is a group of fatal genetic disorders that affect the body's ability to eliminate cellular waste. This malfunction leads to the accumulation of lipids and proteins in cells throughout the body, including those in the brain and eyes. As a result, individuals may experience seizures, vision loss, difficulties with thinking and movement, and ultimately, death..

Neurodegenerative diseases. Neurodegenerative diseases Causes Genetic Pharmacological Brain injury Lifestyle & diet Neuronal hormone depletion X Neurotransmitters degradation Climatic influences Environment factors • • • Management • • Antioxidants Trolox drug levodopa and acetylcholine esterase inhibitors Non-Pharmacological Non-invasive techniques such as neuro-stimulators and modulators Traditional Chinese medicine and diet • • Rise in temperature Extreme and harsh weather Changes in precipitation Heavy metals Pollution Exposure to microorganisms.

Neurodegenerative diseases. Dysfunction in ubiquitin —proteasome pathway Impairment in autophagic -lysosomal clearance Mitochondrial dysfunction and ER stress Protein misfolding and aggregation Deposition of aggregated protein Normal neuron Degenerated neuron.

[Audio] The aging process and environmental factors contribute to the development of neurodegenerative diseases. Aging can lead to deregulation of oxidoreductase activities, resulting in increased DNA damage and genetic and epigenetic deregulation. This indicates an increase in oxidative stress on healthy neuronal cells, causing lipid peroxidation and protein oxidation. The deregulation of neurotrophic factors and neurotransmitters, as well as damage to the cell membrane and loss of mitochondrial function, can all contribute to neurodegeneration. Furthermore, nutrient deficiencies and microglial activation can also play a role in increasing neuroinflammations, leading to deregulation of cytokines and chemokines secretion..

[Audio] In neurodegenerative diseases, proteins fail to fold into their correct three-dimensional structure, leading to the formation of toxic aggregates. This process is observed in various conditions, including Alzheimer's Disease, where beta-amyloid plaques and tau tangles accumulate, causing neuronal damage and death. Similarly, in Parkinson's Disease, alpha-synuclein aggregates form, while in Huntington's Disease, mutant huntingtin protein aggregates accumulate. The key molecular pathways involved in this process include the ubiquitin-proteasome system, heat shock proteins response, and unfolded protein response. These pathways play crucial roles in maintaining protein homeostasis and preventing the accumulation of misfolded proteins. However, in neurodegenerative diseases, these mechanisms are impaired, allowing misfolded proteins to aggregate and contribute to the development of the condition..

Normal Amyloid Precursor Protein secreta* AP peptides Aß oligomers Åggregai6+ Amyloid plaques Tau hyperphosphorylation öggrega+ Neurofibrillary tangles Neuronal dysfunction •suh+ Neurodegeneration.

[Audio] The disruption in the normal regulation of transcription in Alzheimer's disease leads to an imbalance in the expression of genes involved in neuronal survival and synaptic plasticity. This imbalance contributes to the formation of neurofibrillary tangles and amyloid plaques, which are characteristic features of the disease. The nuclear translocation of proteins such as tau and APP also plays a crucial role in the pathogenesis of Alzheimer's disease. Furthermore, the activation of pro-apoptotic pathways, including those involving caspases and calpain, leads to increased apoptosis and neuronal death. Additionally, the formation of reactive oxygen species (ROS) and the activation of microglia contribute to the progression of the disease..

[Audio] Chronic inflammation in the brain can lead to the activation of immune cells called microglia and astrocytes. These activated immune cells release inflammatory molecules, which can contribute to the progression of neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. The key molecular pathways involved in this process include the NFκB signaling pathway, NLRP3 inflammasome activation, and cytokine signaling through molecules like IL-1β, TNF-α, and IL-6..

Which disease?. T-cells activation Gross BBO CNS infiltration NeléåSe cytokine Microglial activation Release inflammatory mediators Inflammation Oamage Myelin sheath kesults Axonal damage Neurodegeneration.

[Audio] The immune system plays a crucial role in protecting the central nervous system by removing injurious stimuli. In response to signals such as toxic insults, infections, or autoimmune attacks, microglia, macrophages, and astrocytes activate to eliminate the threat. This process, known as neuroinflammation, aims to preserve the integrity of the brain. However, in neurodegenerative diseases, this response can become dysfunctional, leading to further damage and exacerbating the condition..

[Audio] In this slide, we are discussing altered cell signaling, a concept that refers to disruptions in normal cellular communication. This can occur through changes in neurotransmitter systems or abnormal signal transduction. For instance, in Parkinson's Disease, there is a disruption in dopamine signaling, whereas in Alzheimer's Disease, the cholinergic system is impaired. Similarly, in Huntington's Disease, BDNF signaling is impaired. These alterations in signaling pathways can have significant consequences for our understanding of neurodegenerative diseases. The key molecular pathways involved include the MAPK pathway, the PI3K/Akt pathway, and cAMP signaling..

Which disease?. Dopaminergic neurons -synuclein accumulatioii Reduced dopamine impaired signaling Dl /D2 receptor dysfunction Ältered cAMP signaling Qisrupteé Motor control pathways Movement disorders.

[Audio] Under physiological conditions, ion channels play a crucial role in regulating various cellular processes. The L-type calcium channel and voltage-gated calcium channel participate in activity-dependent calcium loading, while potassium ATP-sensitive channels and N-methyl-D-aspartate receptors help mediate bursting activity and calcium-stimulated tricarboxylic acid cycle activity. Additionally, ion channels such as D2-AR/NCS1/GIRK-2, KATP, and SK-3 reduce electrical activity. Anti-oxidative enzymes like DJ1 and superoxide dismutase function to control oxidative stress. Calcium-dependent gene expression regulates cellular activity..

[Audio] Premature aging of neurons can lead to progressive cell death, resulting in the loss of neural tissue. This process is observed in various neurodegenerative diseases, such as Alzheimer's, Parkinson's, and ALS. The p53 pathway, apoptotic pathways, and DNA damage response pathways are key molecular mechanisms involved in this process..

Which disease?. Motor neurons SODI mutation Oxidative stress itochondrial dy Energy deficit Activati0ö Apoptotic pathway aspase activation Motor neuron death Muscle weakness.

[Audio] Mutations in proteins involved in the pathways of cell death, such as apoptosis, necroptosis, and autophagy, can lead to the progression of neurodegenerative diseases. The disruption of apoptotic signaling, mitochondrial dysfunction, impaired autophagy, and the activation of the necrosome by stress and inflammation all contribute to neuronal cell death. These molecular pathways play a crucial role in the development of neurodegenerative diseases..

[Audio] På slide nummer 27 vil vi fokusere på mekanismerne bag ferroptose, en særligt destruktiv form for celledød, og hvordan det påvirker hjernen. Ferroptose er en nyere opdagelse inden for celledødsmekanismer og er blevet identificeret som en mulig årsag til neurodegenerative sygdomme såsom Alzheimers og Parkinsons. Ved hjælp af stoffer som erastin, sorafenib, sulfasalazine og glutamat kan vi aktivere ferroptose i hjerneceller og ophobning af jern, som kan være yderst skadelig for cellerne. Systemet xCT, der transporterer cystin og cystein, spiller en afgørende rolle i ferroptose og ved at hæmme denne transport kan man forhindre ophobning af jern og reducere risikoen for ferroptose. Dette kan gøres ved hjælp af jernkelatorer såsom deferipron og deferoxamin. En anden vigtig faktor i ferroptose er pyroptose, en form for inflammatorisk celledød, som kan udløses af fysiologiske eller patologiske påvirkninger og involverer inflammasomer, frigivelse af cytokiner og dannelse af en form for pore i cellemembranen, som kan ødelægge cellen. For at forhindre denne destruktive proces er der udviklet flere typer af hæmmere, såsom RSL3, ML162, ML210 og FIN56, som alle forhindrer jernophobning og dermed reducere risikoen for ferroptose. Derudover kan enzymer som GPX4 og BH4 også beskytte mod ferroptose ved at nedbryde oxiderede lipider. En anden tilgang til at forhindre ferroptose er ved at hæmme lipidperoxidation, hvilket kan gøres ved hjælp af antioxidanter som ubiqionon og vitamin E. Derudover kan enzymet GSDMD nedbryde pyroptose og forhindre dannelse af yderligere skadelige stoffer. Endelig vil vi nævne RTAs, en gruppe af stoffer der kan hæmme oxidativt stress og reducere risikoen for ferroptose, herunder ferrostatin-I, liproxstatin-I og forskellige redox-aktive hæmmere. Det er vigtigt at forstå disse mekanismer for at udvikle effektive behandlinger mod neurodegenerative sygdomme..

[Audio] There are several types of cell death, each with distinct features and mechanisms. One type is programmed cell death, also known as apoptosis, where cells shrink and break down into small packages, which are then eaten by other cells. This process is carried out by caspases. Another type is necroptosis, where cells burst open and release inflammatory signals. This is mediated by RIPK1, RIPK1, and MLKL. Autophagy is another type, where cells recycle their own parts, creating bubble-like structures called vacuoles. This process does not involve DNA damage and is mediated by LC3 proteins. Ferroptosis focuses on damaging mitochondria, involving iron buildup and causing lipid peroxidation. The nucleus remains normal during this process. Pyroptosis is another type, where cells burst but do not swell, releasing inflammatory signals such as IL-1β and IL-18. Finally, there's necrosis, where cells burst due to energy depletion, releasing danger signals..

[Audio] Autophagy plays a crucial role in maintaining the health of our cells by degrading damaged or dysfunctional organelles, such as mitochondria. Damaged mitochondria can accumulate and release toxic compounds, leading to cellular stress and potentially triggering programmed cell death, or apoptosis. Autophagy helps to degrade these damaged mitochondria through the formation of autophagosomes, which then fuse with lysosomes to break down the contents. This selective degradation of damaged mitochondria ensures that healthy mitochondria remain intact and functional. However, when autophagy is impaired, damaged mitochondria can accumulate and contribute to the development of neurodegenerative diseases..

[Audio] Impaired cell motility is a concept that refers to disruptions in the normal functioning of cells, particularly in their ability to move and transport materials within themselves. This can occur through various mechanisms, such as disrupted axonal trafficking, cytoskeletal abnormalities, and impaired vesicular transport. Examples of neurodegenerative diseases that involve impaired cell motility include amyotrophic lateral sclerosis, Alzheimer's disease, and Huntington's disease. The key molecular pathways involved in these processes include kinesin and dynein motor proteins, tau-microtubule interactions, and actin dynamics. These disruptions can lead to progressive damage and degeneration of neurons, ultimately resulting in cognitive decline and dementia..

Which disease?. Mutant Huntingtin AgoregaQi6Ö Disrupted axonal transport 4ffect9 Motor proteins (mpalrS Vesicle trafficking Reduce BDNF transport Synaptic dysfunction.

[Audio] Impaired cell motility plays a crucial role in the development of neurodegenerative diseases, particularly Alzheimer's disease. Certain proteins involved in AD are linked to the regulation of neuronal migration, meaning that the ability of neurons to move and migrate is disrupted, leading to their accumulation in specific regions of the brain. The accumulation of these neurons can lead to the formation of amyloid plaques, which are a hallmark feature of AD. Additionally, it is essential to understand how immune cells migrate to these plaques or areas of inflammation, as this could provide valuable insights into the progression of the disease. The Aβ peptide, a key component of amyloid plaques, increases reactive oxygen species (ROS) levels in migrating neural precursors, causing DNA damage and cell cycle arrest. This ultimately leads to the accumulation of senescent cells in the ventricular-subventricular zone, which are unable to migrate..

[Audio] Environmental factors can contribute to epigenetic changes, leading to alterations in gene expression, which may play a role in the development of neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. For instance, DNA methylation changes have been observed in Alzheimer's disease, whereas histone modifications have been linked to Parkinson's disease. Moreover, microRNA dysregulation has been implicated in ALS. These epigenetic changes can impact various molecular pathways, including those involved in DNA methylation, histone modification, and microRNA processing..

Which disease?. Environmental factors Älte€ DNA methylation ethanges ih Gene expression Affects APP processing ncreases Aß production Neurodegeneration.

[Audio] The initial reactions between oxygen and nitric oxide result in the formation of peroxynitrite, which then converts into hydroxyl radical. This conversion occurs via three pathways: the Fenton reaction, catalase, and glutathione cycle. The resulting hydroxyl radicals initiate a damage pathway, causing nucleic acid damage, lipid peroxidation, and protein structural changes, ultimately leading to neuronal injury..

[Audio] Free radicals, generated within the mitochondria, increase oxidative stress, leading to the formation of reactive oxygen species. ROS cause lipid peroxidation and DNA oxidation, resulting in mitochondrial DNA damage and membrane permeability impairment. This damage disrupts the normal functioning of the mitochondria, causing loss of membrane potential and abnormal protein aggregation. The accumulation of these changes ultimately leads to cell apoptosis and neurodegeneration. Furthermore, impaired mitochondrial function reduces ATP production and disrupts calcium homeostasis, perpetuating further oxidative stress. Additionally, altered excitotoxicity and decreased ubiquitin-proteasome function contribute to the progression of neurodegeneration. Finally, high concentrations of free radicals inhibit the proper functioning of mitochondrial complexes II and IV, exacerbating the damage..

[Audio] Free radicals generated from environmental factors can have devastating effects on our biological systems. They do so by increasing oxidative stress, which impairs glycolysis and the electron transport chain, leading to bioenergetic failure. This failure can result in axonal degeneration and synaptic impairment, ultimately contributing to the development of neurodegenerative diseases. Furthermore, these free radicals can alter gene expression patterns, activating key genes such as PERK, NF-κβ, HO1, HIF-1α, and Mfn-2, which can lead to endoplasmic reticulum stress and decreased neuronal activity. The consequences of this process include excitotoxicity, calcium dysregulation, and synaptic plasticity deficits, all of which contribute to the progression of neurodegenerative diseases..

[Audio] Free radicals are generated within cells, primarily causing neurodegenerative disease pathogenesis. The accumulation of these free radicals increases oxidative stress, which subsequently decreases the antioxidant defense system. This decline in antioxidant defense allows DNA damage to occur, triggering further cellular dysfunction. The damaged DNA then leads to defective electron transport chain, increased ATM activity, and increased gamma-H2AX activity, a marker for DNA damage. The activation of key pathways, including NF-kappa beta and p53, drives cell death signaling. p53 activation results in increased p21 activity, which modulates the expression of CDKs and cyclins, ultimately regulating the cell cycle. Furthermore, NF-kappa beta activation contributes to mitochondrial impairment by releasing pro-inflammatory cytokines, while cell death signaling opens the mitochondrial permeability transition pore. Ultimately, mitochondrial dysfunction results in cell apoptosis via caspase activation, cytochrome C release, and PARP recruitment, leading to neurodegeneration driven by DNA damage, cell-cycle arrest, inflammation, and neuronal apoptosis..

[Audio] Free radicals play a crucial role in the development of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebral ischemia, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, epilepsy, and brain injury progression. The accumulation of free radicals induces oxidative stress, which triggers a cascade of events leading to cellular damage and ultimately contributes to the progression of these diseases..

[Audio] The importance of signaling pathways in maintaining overall health cannot be overstated. These pathways play a crucial role in facilitating interactions between cells, tissues, and organs, whether through simple communication or complex biological processes. In the context of neurodegenerative diseases, disruptions in these pathways can have devastating consequences, leading to the progressive decline of cognitive and motor functions. It is essential that we acknowledge the profound impact signaling has on our lives..