Harald Hampel, MD, PhD, MSc’s Post

The amyloid pathway and the accumulation of neurotoxic beta-amyloid (Aβ) and phosphorylated tau proteins are intrinsically linked to oxidative stress, creating a cycle that exacerbates neuronal damage. Here’s how these processes interconnect: 1. Beta-Amyloid Aggregation and Oxidative Stress: • The accumulation of beta-amyloid plaques, particularly the aggregated form, can directly generate oxidative stress. Beta-amyloid is known to induce reactive oxygen species (ROS) through its interaction with cellular components, especially mitochondria. As Aβ aggregates, it disrupts mitochondrial function, resulting in excess ROS production, which damages cellular lipids, proteins, and DNA. • Aβ can also bind to and activate receptors on neurons and glial cells, such as the receptor for advanced glycation end products (RAGE), which further promotes oxidative stress and inflammation. 2. Phosphorylated Tau and Oxidative Damage: • Phosphorylated tau, typically associated with neurofibrillary tangles, contributes to oxidative stress by destabilizing microtubules and disrupting intracellular transport. This impairment affects mitochondria, which then leak ROS and further exacerbate oxidative stress. • Oxidative stress can promote abnormal tau phosphorylation, creating a feedback loop in which tau-induced oxidative stress accelerates tau pathology, worsening neuronal damage. 3. Excitotoxicity and Oxidative Stress in Neurons: • Both Aβ and phosphorylated tau disrupt calcium homeostasis and promote excitotoxicity, particularly in excitatory neurons of the hippocampus and entorhinal cortex. Excitotoxicity leads to increased calcium influx, which overactivates enzymes that produce ROS and promote oxidative damage. • This excitotoxicity causes further release of glutamate, leading to a vicious cycle of neuronal activation, calcium influx, and oxidative damage. 4. Role of Oxidative Stress in Widespread Neurodegeneration: • In Alzheimer’s disease and related disorders, oxidative stress acts not only as a consequence of amyloid and tau pathology but also as a catalyst for the spread of these pathological changes to other brain areas. As oxidative damage accumulates, neurons become increasingly vulnerable to Aβ and tau toxicity, leading to progressive degeneration of critical brain regions. 5. Feedback Loop Between Oxidative Stress and Pathology: • Oxidative stress and amyloid-tau pathology perpetuate each other. ROS can promote the aggregation of Aβ and tau phosphorylation, while aggregated Aβ and tau pathology increase ROS production. This feedback loop accelerates neurodegeneration, leading to progressive cognitive decline. Overall, oxidative stress is both a result and a driver of beta-amyloid and tau pathology. This cycle underscores the importance of managing oxidative stress as a potential therapeutic approach in diseases involving the amyloid pathway, as reducing ROS may help mitigate beta-amyloid aggregation, tau pathology, and the result neuron loss

Recent research has provided a comprehensive analysis of astrocyte changes throughout Alzheimer's disease (AD) progression. Astrocytes, crucial for brain health, have been less studied compared to neurons. This study, published in Nature Neuroscience, utilized single-nucleus RNA sequencing on over 600,000 nuclei from various brain regions to map astrocyte responses. Findings revealed distinct astrocyte subpopulations and new intermediate states, highlighting their dynamic role in AD. This research enhances understanding of AD and may guide future therapeutic strategies. Further studies will explore interactions between astrocytes and other brain cells to better understand AD neurodegeneration.

Yale scientists have leveraged advanced sequencing technologies to create a detailed cell atlas of brains affected by Parkinson’s disease, revealing significant neuroinflammation as a key factor. Using single-cell transcriptomics and proteomics, they found elevated levels of immune cells, such as T cells and microglia, in Parkinson’s-affected brains. This inflammation, along with a decreased expression of protein-chaperone molecules that help prevent protein clumping, suggests new therapeutic avenues to potentially reduce the abnormal protein aggregations associated with Parkinson's. Comparing Parkinson’s and Alzheimer’s brain cells, researchers noted distinct patterns in how each disease affects neurons, indicating separate treatment pathways. The cell atlas they’ve developed is expected to support future research, offering a foundational map for studying the disease’s progression. As a next step, Yale researchers plan to explore early-stage brain samples, as well as blood and spinal fluid, to identify markers that could lead to preventative clinical trials for Parkinson’s. #neurology #parkinsons #inflammation With the Specialist combines artificial intelligence with a board certified neurologist to enhance neurological care, bringing the neurology consult to you. #withthespecialist #aiinhealthcare #innovation https://lnkd.in/g5we6m3p https://lnkd.in/gExrwg2P

Memory loss, confusion, speech problems – Alzheimer’s disease is the most common cause of dementia, affecting about 35 million people worldwide, and the number is growing. The protein amyloid beta, which occurs naturally in the brain, plays a central role in the disease: It accumulates in patients in insoluble clumps that form plaques between neurons in the brain, damaging them. Researchers at the Max Planck Institute (MPI) for Multidisciplinary Sciences have now shown that, in addition to neurons, special glial cells in the brain also produce amyloid beta. This finding could open up new avenues for future therapies. A hallmark of Alzheimer’s disease is the accumulation and aggregation of the protein amyloid beta into damaging plaques. Current research shows that not only neurons but also insulating glial cells – the oligodendrocytes – produce significant amounts of amyloid beta. Amyloid beta must exceed a certain threshold for plaques to form. There is no cure for Alzheimer’s disease. However, there are therapeutic approaches to reduce the amyloid plaques in the brain. That can slow down the progression of the disease, but it cannot reverse or stop it. “Until now, neurons were thought to be the main producers of amyloid beta and have been the main target for new drugs,” explains Klaus-Armin Nave, Director at the MPI for Multidisciplinary Sciences. Results from his Department of Neurogenetics have now shown: In addition to neurons, special glial cells – called oligodendrocytes – play an important role in plaque formation. “One of the tasks of oligodendrocytes is to form myelin – an insulating layer – and wrap it around the nerve fibers to speed up signal transmission,” explains Andrew Octavian Sasmita, one of the first authors of the study now published in Nature Neuroscience and a former PhD student in Nave’s team. In a previous study, the Göttingen researchers had already discovered that defective myelin of oligodendrocytes exacerbates Alzheimer’s disease. Do glial cells play an even greater role in the disease than previously thought? “We have now shown that although neurons are the main producers of amyloid beta, oligodendrocytes also produce a significant amount of the protein which is incorporated into plaques,” says Sasmita. A research group led by Marc Aurel Busche of the University College London (England) recently came to similar conclusions #clinicalpsychology #neuroimaging #psychopathology #neuroscience #reserchflash

🌟💬 Xtalks Spotlight: Understanding the complexities of brain function is crucial for advancing #Alzheimer’s treatments. Biomarkers are key, offering insights into pathophysiology, early detection, progression tracking, and treatment efficacy. Excitingly, EEG biomarkers show promise in unraveling neurophysiological changes in Alzheimer’s. 🧠 In our recent Xtalks Spotlight interview, Christopher (CJ) Barnum PhD, from INmune Bio Inc., and Brian Murphy, PhD, from Cumulus Neuroscience, delve into the significance of EEG biomarkers in Alzheimer’s research. They also share groundbreaking results from a pilot study using the Cumulus Neuroassessment Platform, highlighting its potential in enhancing our understanding and treatment of Alzheimer’s. ➡️ Read the full interview here: https://buff.ly/4aqp9vK #CNSTrials #DigitalBiomarker #DigitalBiomarkers #XtalksSpotlight #NeuroscienceTrials #NeuroscienceClinicalTrials #CNSDrugDevelopment #AlzheimersDiseaseTrials #NeurodegenerativeDisease

Study focus = “For TBI, the pathology evolves and changes over time, meaning that a single protein or receptor may be upregulated at one phase of the injury, but not two weeks later,” said Sarah Stabenfeldt. “This dynamic environment makes developing a successful targeting strategy complicated.” *Note: Two of those changes: BBB and mitochondria* (The blood-brain barrier (BBB) barrier is a barrier between the vascular and brain tissue. In a healthy individual, the BBB tightly regulates nutrient and waste exchange from the blood to the brain and vice versa, essentially compartmentalizing the brain/central nervous system.) (Mitochondria are the energy powerhouse of the cell) Findings = “It was really interesting to see that proteins involved in neurodegenerative diseases were detected at 7 days post-injury, but not at the earlier, 1-day post-injury time point." Initial injury = When a TBI occurs, the initial injury can disrupt the BBB, which triggers a cascade of cell death, torn, disrupted tissues and debris. Long-term injury= The long-term injury causes inflammation and swelling, and results in the immune response to spring into action, but also can lead to an impairment of the brain’s energy sources, or can choke off the brain’s blood supply, leading to more neuronal cell death and permanent disability. Result = It may also begin to explain why people who have had a TBI are more susceptible to developing neurodegenerative diseases like Parkinson’s and Alzheimer’s later in life. #CTE #brainhealth #neurology #BBB #mitochondria #neurofit

YALE SCIENTISTS IDENTIFY POTENTIAL TREATMENT FOR UNTREABABLE 'SMOOTH BRAIN' DISORDERS Lissencephaly is a rare spectrum of genetic disorders characterized by the brain’s failure to form its typical folds. These disorders often result in seizures and intellectual disabilities, and there are currently no treatments available. However, a new Yale study has uncovered a molecular mechanism responsible for certain forms of lissencephaly and identified a drug capable of both preventing and reversing brain malformations in organoids—miniature 3D models of developing brains used to study early brain development. Published in Nature, the findings may provide a promising target for future treatments, according to the researchers. “Lissencephaly belongs to a group of disorders we call malformations of cortical development, meaning the normal development and structure of the brain is disrupted,” said Angeliki Louvi, professor of neurosurgery and of neuroscience at Yale School of Medicine (YSM) and co-senior author of the study. “They come about because certain genes that are very important for brain development are affected by rare mutations.” The new study builds on gene discovery research conducted by the Yale Program in Neurogenetics and pioneered by co-senior author Murat Gunel, Sterling Professor of Neurosurgery and professor of genetics and of neuroscience at YSM. For years, the program has collected blood samples from patients affected by brain malformations in order to identify genetic mutations associated with their disorders. “It has been 17 years since the first family enrolled in our research, and they happen to be one of the families in the study,” said Kaya Bilguvar, associate professor adjunct of neurosurgery and genetics at YSM, and co-senior author of the study. “This level of collective commitment, including by patients and families, is inspiring.”... It will be important to explore potential clinical applications of mTOR activators in this spectrum of disorders as well, Bilguvar added, as benefiting patients through basic discoveries is the program’s ongoing motivation. Source: https://lnkd.in/gzm8r6jh

Innovations in neuroscience are pivotal for advancing our understanding of brain health and addressing complex neurodegenerative conditions. Mayo Clinic's recent advancements, including cutting-edge developments in neuroscience, highlight the field's ongoing evolution. At the McDonnell Genome Institute, we're aligned with this mission through our commitment to groundbreaking research in neurobiology, leveraging high-plex proteomics, genomics, and cell engineering to uncover new insights into neurological diseases and aging. These innovations fuel our shared goal: translating scientific discovery into real-world impact for patients. https://lnkd.in/g29f_3CF #neuro #genomics #proteomics

Happy to share with you our latest paper in Molecular and Cellular Neuroscience! We used patient-derived cells to generate patient specific microglia cells to study microglial responses in Alzheimer's Disease. These patient-derived microglia showed higher activity, meaning they were more responsive, even without stimulation. This method provides a new way to study how brain immune cells behave in Alzheimer’s and could help us develop personalized treatments in the future. I’m so proud of this work and grateful to my collaborators for their incredible contributions! 🙌 📖 Read the full paper here: https://lnkd.in/gbBhhc27 #AlzheimersResearch #BrainInflammation #Microglia #Research #iPSC #iMG

Pathophysiology of Alzheimer's Disease: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of abnormal proteins and neuronal loss. The key pathological features include: 1. Beta-Amyloid Plaques: Extracellular deposits of beta-amyloid protein disrupt cell communication. These plaques are toxic to neurons, contributing to cell death and synaptic dysfunction. 2. Neurofibrillary Tangles: Intracellular aggregates of hyperphosphorylated tau protein disrupt the cytoskeleton and impair intracellular transport, leading to cell death. 3. Neuronal Loss and Synaptic Dysfunction: Loss of neurons and synapses in the hippocampus, temporal lobes, and parietal lobes impairs memory and cognitive function. 4. Cholinergic Dysfunction: A reduction in acetylcholine (a neurotransmitter important for memory and learning) is observed due to degeneration of cholinergic neurons. 5. Brain Atrophy: Chronic loss of neurons leads to atrophy, particularly in the hippocampus, entorhinal cortex, and association cortices. --- Imaging Findings in Alzheimer's Disease: CT Scan: General Features: Cortical Atrophy: Widened sulci (grooves) and narrowed gyri (ridges), especially in the temporal and parietal lobes. Ventricular Enlargement (Hydrocephalus ex vacuo): Enlargement of the lateral ventricles due to brain tissue loss. Medial Temporal Atrophy: Early changes include atrophy of the hippocampus and entorhinal cortex. Role: CT is typically used to exclude other conditions (e.g., tumors, subdural hematomas, or strokes) and is not sensitive for early AD changes. --- MRI: Preferred Imaging Modality for Alzheimer's due to higher resolution and sensitivity. 1. Structural Changes: Medial Temporal Lobe Atrophy: Specific to AD, involves the hippocampus, amygdala, and entorhinal cortex. Global Cortical Atrophy: Prominent in the temporal and parietal regions, sparing the occipital lobe. White Matter Lesions: Associated with aging or vascular pathology but may coexist in AD. 2. Functional and Advanced Techniques: Diffusion Tensor Imaging (DTI): Shows microstructural white matter changes. Functional MRI (fMRI): Detects altered brain activity in memory-related networks. Volumetric MRI: Measures hippocampal volume loss, an early biomarker for AD. --- Comparison of CT vs. MRI in Alzheimer's: In summary, CT is limited to gross structural changes, while MRI provides a more detailed view of early and specific Alzheimer's-related changes, particularly in the hippocampus and medial temporal lobes.