RCSI Neurodegenerative Processes PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Neurodegenerative Processes [email protected] [email protected] Class Year 2...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Neurodegenerative Processes [email protected] [email protected] Class Year 2 Semester 1 Course CNS Code CNS Title Neurodegenerative Processes Lecturer Niamh Connolly (RCSI-IE): Dr. Colin Greengrass (RCSI-BH) Date 27.11.2023  LEARN THE CONTENT OF Outline the brain regions first affected in the most THIS SLIDE common neurodegenerative disorders LEARN THE MECHANISM /SYSTEM/ PRINCIPLE SHOWN ON THIS SLIDE, BUT NOT ALL THE DETAILS Outline the neuropathology and biochemistry of Alzheimer’s Disease PROVIDES CONTEXT OR LINKED CONTEXT. READ ONCE TO ESTABLISH CONTEXT Discuss the different risk factors for Alzheimer’s DON’T FORGET THE SIGNS Disease List the most common drugs used for the treatment of Alzheimer’s Disease Describe the disease concept and pathophysiology of Prion diseases Neurodegenerative disorders You don’t have to learn the content of this diagram Brain regions Aggregating proteins Genetics Hallmarks of neurodegenerative diseases Characteristic aggregating proteins, genes linked to and affected brain regions in NDDs  Neurodegeneration often affects specific areas of the brain initially, with other areas affected later. Disease First affected region(s) Corresponding clinical features Alzheimer’s Disease Cerebral cortex, basal ganglia, Dementia - Memory loss, hippocampus disorientation, mood changes, communication difficulties. Parkinson’s Disease Basal ganglia, midbrain (substantia Slow movements, tremor, rigidity nigra) Huntington’s Disease Basal ganglia (striatum) Uncontrolled movements Amyotrophic Lateral Sclerosis (ALS; Motor neurons Weakness and paralysis Motor neuron disease) Creutzfeldt-Jakob Disease (CJD) Cerebral cortex, basal ganglia, Dementia, movement disorders cerebellum Amended from: Molecular Pathology, Coleman, Academic Press  Dementia Significant loss of intellectual abilities such as memory, concentration and judgement Severe enough to cause impairment in daily activities Not temporary confusion or forgetfulness Typically progresses to become worse over time Many neurodegenerative disorders are associated with dementia Alzheimer’s is the leading cause of dementia (dementia is not the same as Alzheimer’s) Neurodegenerative Disorders Gradual dysfunction of neurons over time, eventually leading to the death of these neurons e.g. Alzheimer’s, Parkinson’s, Huntington’s diseases Chronic, progressive, pathological disorders Sporadic and hereditary (familial) forms Neurodegenerative Disorders Neuronal cell death Progressive loss of structure or function of neurons, including their death. Pathological protein aggregation Accumulation of abnormally folded proteins, which form insoluble fibrils and toxic aggregates. Synaptic and network defects Synaptic failure is considered an early event in the pathogenesis of several neurodegenerative disorders. Neurodegenerative Disorders Often involves accumulation of aggregated proteins e.g., AD (Amyloid β, Tau); PD (α- synuclein) Aggregates can be directly toxic Aggregates can induce harmful signalling pathways Excitotoxicity Neuroinflammation Neurodegenerative Disorders DNA and RNA defects Mutations result in dysfunctional proteins within cellular pathways Play a critical role in the development and progression of neurodegenerative diseases Altered energy homeostasis Mitochondrial dysfunction and altered energy metabolism in neurons can lead to energy deficits, contributing to cell death and neurodegeneration. Neurodegenerative Disorders Cytoskeletal abnormalities The neuronal cytoskeleton is crucial for maintaining cell shape, transporting organelles, and intracellular signalling. Disruptions in the cytoskeletal structure can impair these functions and contribute to neurodegeneration. Aberrant proteostasis A balance in the synthesis, folding, trafficking, and degradation of proteins is essential for neuronal survival. Impairments in proteostasis including are implicated in neurodegenerative diseases. Type of Dementia % of Cases Most at Risk Key Symptoms Pathophysiology Progression Lifespan Post-Diagnosis Memory loss, Especially over age 65; Amyloid plaques and disorientation, mood Alzheimer's higher risk in women, neurofibrillary tangles Gradual and continuous 4-8 years, can vary 60-80% changes, Disease family history, APOE ε4 causing neuronal death decline. widely communication gene carriers. and brain atrophy. difficulties. Older adults with stroke Brain damage due to Impaired judgment, or cardiovascular cerebrovascular disease Stepwise or fluctuating, 5 years on average, but inability to plan, Vascular Dementia 10-20% disease risk factors like causing localised depending on vascular dependent on stepwise decline in hypertension, diabetes, infarctions or chronic events. cardiovascular health. cognitive abilities. smoking. ischemia. Presence of Lewy Adults over 50; more Visual hallucinations, bodies (alpha-synuclein Lewy Body Gradual but more rapid 5-10% common in men, sleep disturbances, aggregates) in neurons 5-8 years Dementia than Alzheimer's. possible family history parkinsonian symptoms. affecting cognitive and motor functions. Degeneration of frontal Individuals 45-65 years Behavioral changes, Frontotemporal and temporal lobes, 6-8 years, can vary 2-5% old; family history of language difficulties, Rapid progression. Dementia often with tau or TDP- based on subtype FTD or ALS significant. emotional blunting. 43 protein aggregates. PRINCIPLES TO LEARN – MOST COMMON, Forms of Dementia GENERAL PROGNOSIS AND PROGRESSION, MAIN SYMPTOMS AND DIFFERENCES  Alzheimer’s disease (AD) Most common cause of dementia in adult life Affects many million people world-wide (44 million cases; $604 billion/year) First reported by Alois Alzheimer in 1906, who described both clinical and pathological data Auguste D. (the first description of AD) Brain atrophy in AD Symptom progression Mild cognitive Mild Symptoms impairment (MCI) Prodromal AD Severe Symptoms Confusion and memory loss Loss of speech Personality changes Loss of appetite Loss of bladder and bowel control Judgement problems Complete dependence on caregiver Difficulties with routine tasks Getting lost or disoriented in familiar places Moderate Symptoms Difficulty with personal care such as bathing and dressing Anxiety, agitation and paranoia Insomnia or sleep disturbances Wandering and pacing Trouble with or inability to recognise familiar faces Alzheimer’s pathology: Two hallmarks Neurofibrillary tangles Amyloid plaques Alzheimeris disease Amyloid Plaques https://www.ncbi.nlm.nih.gov/books/NBK566126/ Neurofibrillary Tangles https://thebrain.mcgill.ca/flash/d/d_08/d_08_cl/d_08_cl_alz/d_08_cl_alz.html  Initiation – Beta Amyloid Amyloid Precursor Protein (APP) Processing: Abnormal processing of APP Beta-Amyloid Aggregation: Imbalance in Aβ production and clearance results leads to the production of beta-amyloid (Aβ) peptides. in aggregation and formation of amyloid plaques. Tau Protein Pathology Hyperphosphorylation of Tau Protein: Abnormal phosphorylation detaches Formation of Neurofibrillary Tangles: Hyperphosphorylated tau forms paired tau from microtubules. helical filaments that aggregate into tangles inside neurons. Neuronal and Synaptic Dysfunction Synaptic Damage: Amyloid plaques and neurofibrillary tangles disrupt Neuronal Loss: Progressive neuronal death, especially in the hippocampus synaptic function, impairing neuronal communication. and cortex, leading to brain atrophy. Neuroinflammation Activation of Glial Cells: Microglia and astrocytes respond to amyloid and tau Chronic Inflammation: Prolonged glial activation contributes to a neurotoxic pathologies. environment, exacerbating neuronal damage. PATHOPHYSIOLOGY OF ALZHEIMER DISEASE Amyloid Precursor Protein APP is a large transmembrane protein that normally contributes to neural growth and repair Under normal physiological conditions, APP is involved in neuron growth, survival, and post-injury repair. It is integral to the development of the nervous system and synaptic plasticity.  Beta (β) amyloid In AD there is a pathophysiological extracellular accumulation of β-amyloid = Amyloid plaques Hard, insoluble plaques between cells, leading to a local, inflammatory tissue response Monomers or oligomers of β-Amyloid may be more ? toxic to cells β-amyloid is a cleavage product of a larger protein called the Amyloid Precursor Protein (APP) Initiation of Alzheimers – Amyloid Dysfunction Amyloid Precursor Protein (APP) Processing: Abnormal processing of APP leads to the production of beta-amyloid (Aβ) peptides. Beta-Amyloid Aggregation: Imbalance in Aβ production and clearance results in aggregation and formation of amyloid plaques.  Beta (β) amyloid Pathogenic Cleavage of APP INSOLUBLE FORM Produces Aβ42. Initiates AD pathology. β-Amyloid Accumulation Extracellular amyloid plaques. Hallmark of AD pathology. Plaque Formation and Inflammation Hard, insoluble fibrils. Disrupt cell function. Provoke inflammatory response. Toxicity of β-Amyloid Forms Formation: β-Amyloid monomers aggregate to form soluble, neurotoxic oligomers. Synaptic Disruption: Oligomers bind to neurons at synaptic sites, impairing communication and plasticity, crucial for memory. Cytotoxic Effects: Induce oxidative stress. Disrupt calcium homeostasis. Trigger cell death pathways. Outcome: Soluble oligomers disrupt neuronal membrane integrity, leading to synaptic loss and neuron death, contributing to cognitive decline in AD.  You don’t have to learn the content of this diagram Secretases Proteases that cleave the APP α secretase Normal processing of APP is by -secretase then -secretase (generates A1-40) β secretase In Alzheimer’s -secretase cleaves in extracellular and -secretase in γ secretase transmembrane generating abnormal A1-42 form which is “amyloidogenic” β-amyloid is formed through the enzymatic cleavage of a larger protein, the Amyloid Precursor Protein (APP), by β-secretase and γ- secretase enzymes. Membrane NTF: N-terminal fragment CTF: C-terminal fragment  AICD: APP intracellular domain CTF: C-terminal fragment sAPP: soluble APP Non-amyloidogenic APP Amyloidogenic Normal APP You don’t have to learn the https://www.ncbi.nlm.nih.gov/books/NBK566126/ content of this diagram processing  AICD: APP intracellular domain CTF: C-terminal fragment You don’t have to sAPP: soluble APP learn the content of this diagram Non-amyloidogenic APP Amyloidogenic Abnormal APP processing https://www.ncbi.nlm.nih.gov/books/NBK566126/ Neurofibrillary tangles Insoluble fibres inside neurons (intracellular) Consist of an abnormally phosphorylated protein – Tau (p-Tau) Tau is (normally) involved in the function of the microtubule system Microtubules transport proteins and organelles inside neurons In Alzheimer’s disease, the microtubule structure collapses https://www.ncbi.nlm.nih.gov/books/NBK566126/ Interactions Between Amyloid/Neurofibrillary Pathologies Mutual Promotion: Aβ peptides can induce tau pathology (cross- seeding), while tau tangles may exacerbate Aβ aggregation. Synaptic Dysfunction: Both Aβ and NFTs disrupt synaptic signalling and plasticity, leading to cognitive decline. Neuroinflammation: Aβ and NFTs activate glial cells, resulting in inflammation that damages neurons and supports further pathology.  Tauopathies Disorder Symptoms Underlying Pathophysiology Presence of argyrophilic grains composed of May be asymptomatic, or present with Argyrophilic Grain Disease (AGD) abnormally phosphorylated tau protein, cognitive decline, especially in memory. predominantly in the hippocampus and amygdala. Neurofibrillary tangles composed of tau protein, Progressive Supranuclear Palsy Difficulties with balance, movement, vision affecting brainstem, basal ganglia, and frontal (PSP) (particularly downward gaze), and dementia. cortex regions. Accumulation of Pick bodies, which are tau protein Pick's Disease (Frontotemporal Behavioral changes, personality alterations, aggregates in neurons, affecting the frontal and Dementia) and language difficulties. temporal lobes. Mutations in the MAPT gene on chromosome 17 Frontotemporal Dementia and Behavioral changes, cognitive decline, and leading to abnormal tau protein that forms Parkinsonism linked to parkinsonism (movement difficulties). aggregates, causing neuronal dysfunction and Chromosome 17 (FTDP-17) brain atrophy. Familial AD (Early Onset) Age of onset consistently