Parkinson disease and Alzheimer's diseasePrepared by: Sagar Khatiwada MBBS, MD

Introduction to nervous systemTectum: it is the roof of midbrain.Tegmentum: covering in Latin. It is the part in brain stem that is ventral to cerebral aqueduct. The contrast of tectum and tegmentum is that, tegmentum is ventral while tectum is dorsal. All parts of brain in fetus develops further by folding, thickening etc. but tegmentum remains same in fetus and adult. In ventral and lateral part there are other structures aswell like crus cerebri, but they are not called tegmentum because they are not part of primitive neural tube but grows as projection from cerebral cortex.So parts that were present since neural tube, they remains relatively unchanged in fetus and adulthood are tegmentum.

Ventral to ventricular system: tegmentum, origins from primitive neural tube, in fetus and adult no changesIt is bounded by substantia nigra to cerebral aqueductDorsal to ventricular system: tectum. It forms roof of the midbrain, in cross sectional position. Colliculus which thincken and folds in adult is part of tectum

Subarachnoid cisternsIn certain areas of brain, the piamater and arachnoid mater are separated widely which contains CSF known as cisterns.

Reticular formationIt is the intrinsic system of brain stemIt consists of diffuse network of neuron deep in the tegmentum that influence and modifies sensory and motor systems and plays a key role in consciousness and central pattern generation.Central pattern generation means the complex movement generation like coughing, vomiting etc.The vast majority of neurons here are interneurons that have multiple efferent projections.

Parts of reticular formations:Lateral zoneMedial zoneNeurotransmitter systemLateral Zone:Recieves sensory impulse from spinoreticular tract. Its neuron project to medial zone for motor function.Medial zone: has efferent projection to motor output. Reticulospinal tract.

Lateral zoneMedial zonehypothalamusAminergic and cholinergic nucleithalamusBasal gangliacerebellumCerebral cortexSensory impulseComplex efferent motor impulseReticulospinal tractSpinoreticular tract

Neuro transmitter systemDopaminergic system:Nucleus accumens to prefrontal cortex, amygdala and hypothalamus.Substantia nigra to caudate, putamenMERAD : motivation, emotion, reward, addiction, depressionDepressed, emotional, addiction, motivation, reward { dream}Noradrenergic system:Locus coeruleus [ blue spot ] to cerebellum, cerebrum , basal ganglia and thalamus .Release of NE: Tonic release: continuous phasic release: on the basis of necessityAROUSAL AND SLEEP WAKE CYCLESerotoninergic system:Raphe nucleus to prefrontal cortex, thalamus, basal ganglia etc.Sleep, apetite, modulation of pain, wakefullness, agression.

Alzheimer disease: In Alzheimer disease (AD), LC neurons are very susceptible to neurodegeneration and a loss of theseneurons affects the NE signaling in the entire CNS. Interestingly, NE suppresses neuroinfl ammation, and its signaling canactivate microgliaMicroglial activation is key for the clearance of neurofibrillary tangles and A deposits, and neuroinflammation is thought to be one of the pathological mechanisms in AD. Furthermore, the loss of noradrenergic neurons from the LC in AD exacerbates the neuroinflammation and hinders the clearance of debris by microglia.

Substantia nigraSubstantia nigra: it is a island of neuronal cells which consists of monomines. It is situated in midbrain. They are black due to high amount of melanin of dopaminergic neurons.

Cytoskeleton and tau proteinThe cell consists of cytoskeleton which provide mechanical structure of cellNanofilament, micro filaments, intermediate filaments and microtubules are the cytoskeleton. They are named on the basis of their diameter. Nanofilament being the the thinnest in diameter. Microfilament [ upto 7 nanometer], intermediate filament [ upto 10 nanometer] and microtubule [ upto 25 nano meter] in diameter.Actin, myosin are example of microfilaments.Tau protein are the protein which binds cytoskeleton in its fixed position.Tau protein has three or four binding sites for cytoskeleton.

synucleinSynuclein are proteins expressed in neural tissue { sinew}It consist of highly conserved lipid binding alpha helical motif in all types of synuclein.The folded synuclein alpha forms amyloid responsible for deposition in substantia nigra of brain.

Alpha synucleinPredominantly present in neocortex, hippocampus, substantia nigra, thalamus and cerebellum.Neuronal predominance, but also found in neuroglial cells.Present inside nucleus, mostly are intranuclear synuclein however found in presynaptic terminal in both free and membrane bound forms and some in mitochondria.

Alpha synucleinThe n-terminus of alpha synuclein binds with phospholipid of cellmembrane.The COOH- terminus of synuclein binds with synaptobraevinFunction of synuclein:For vesicle exocytosisThey also serves as the chaperone protein.

Figure 14-2 The working of a chemical synapse, the motor nerve ending, including some of the apparatus for synthesis of transmitter. The large intracellular structures are mitochondria. Acetylcholine (ACh), synthesized from choline and acetate by acetyl coenzyme A (acetyl CoA), is transported into coated vesicles, which are moved to release sites. A presynaptic action potential that triggers influx of calcium through specialized proteins (Ca2+ channels) causes the vesicles to fuse with the membrane and discharge transmitter. Membrane from the vesicle is retracted from the nerve membrane and recycled. Each vesicle can undergo various degrees of release of contentsfrom incomplete to complete. The transmitter is inactivated by diffusion, catabolism, or reuptake. The inset provides a magnified view of a synaptic vesicle. Quanta of ACh together with adenosine triphosphate (ATP) are stored in the vesicle and covered by vesicle membrane proteins. Synaptophysin is a glycoprotein component of the vesicle membrane. Synaptotagmin is the vesicle's calcium sensor. Phosphorylation of another membrane protein, synapsin, facilitates vesicular trafficking to the release site. Synaptobrevin (vesicle-associated membrane protein [VAMP]) is a SNARE protein involved in attaching the vesicle to the release site (see also Fig. 14-3 ). CAT, choline acetyltransferase.

Model of protein-mediated membrane fusion and exocytosis. A, Release of acetylcholine from vesicles is mediated by a series of proteins collectively called SNARE proteins. Synaptotagmin is the neuronal calcium receptor that detects entry of calcium. Synaptobrevin (i.e., vesicle-associated membrane protein [VAMP]) is a filament-like protein on the vesicle. B, During depolarization and entry of calcium, synaptobrevin on the vesicle unfolds and forms a ternary complex with syntaxin/SNAP-25. This process is facilitated by phosphorylation of synapsin, also present on the vesicle membrane. C, Assembly of the ternary complex forces the vesicle in close apposition to the nerve membrane at the active zone with release of its contents, acetylcholine. The fusion is disassembled, and the vesicle is recycled. Clostridial toxins, including tetanus and botulinum, inhibit the release of acetylcholine and cause paralysis of muscles. The toxin consists of a light (Lc) and heavy (Hc) chain. D, The first stage in intoxication is interaction of the toxin with a thus far unidentified receptor. E, This is followed by internalization of the toxin within the vesicle and release of the light chain from the vesicle. The liberated Lc cleaves a variety of SNARE proteins, depending on the type of toxin released, thereby preventing assembly of the fusion complex and thus blocking release of acetylcholine

Amyloid proteinAmyloid: a hard waxy deposit consisting of protein and polysacchride which is deposited after degeneration. Amyloid means starch. During its discovery, it was mistaken to be a starch.It is the misfolded protein or abnormally folded protein.They are beta sheet quaternary structuresSteric zipper interface: the beta sheet interdigitate and forms compact dehydrated interface.They disrupt physical architecture of cell when they get deposited. And undergo cellular apoptosis.The misfolded protein are degraded by ubiquitin which identify such proteins and pack in proteosome for proteolysis.And some heat shock protein like chaperone are responsible for unfolding or folding of protein. Some protein may denature and fold, this pathological condition is repaired by chaperones.So a pathologically folded protein are either degraded by ubiquitin proteolysis or repaired by chaperone. If these two system fails, the folded proteins deposition occurs. This deposited protein which are pathological fold, are called amyloid protein.

Prions:Misfolded protein which are infective as they can propagate exponentially in host by inducing the misfolding of the protein of host.They finally form amyloid foldsOne of the example of prion disease is bovine spongiform encephalopathy.

Tangles and lewy bodyThey are hyper phosphorylated tau protein deposits.Lewy body: they are the complex of tangle and synuclein. As we know the deposited protein in brain are cleared by ubiquitin or repaired by chaperone while some being taken up by microglia. The uptake of microglia is activated by epinephrine. But these lewy bodies or protein deposits are not able to be dissolved by ubiquitin nor can be repaired by chaperone, hence they change the architecture and physical function of a cell. This results in induction of apoptosis of cell.

Arousal the variety of stimuli, specially somatosensory excites reticular system that is responsible for arousal.The lesion in midbrain lead to failure of arousal and sometimes lead to coma.Less severe dysfunction causes confusional states, in which consciousness is clouded and patient is sleepy, inattentive and disoriented.Uncal herniation of temporal lobe into ambient cistern sorrounding the midbrain can compress third cranial nerve.

Pathophysiology of parkinson disease:The genetic defect lead to mis folding of alpha synuclein.The misfolded synuclein complex form amyloid.These amyloid deposits in the substantia nigra of brain stem.Substantia nigra undergo apoptosis due to such deposits.Hence, there would be very less cell producing dopamine.This leads to parkinsonian syndrome. [ rigidity, bradykinesia, postural instability and peel rolling tremor]

Synuclein is a protein that function as chaperone and tau protein [ they are linked with synaptobraevin] .Synuclein has two structure one is alpha helical and other is beta sheeted.Alpha helical is more in normal condition but during pathology, the protein gets detached from phospholipid and undergo modification to beta sheet. This is faboured by abnormal phosphorylation, amination glycation etc. as they from a complex beta sheet, they becomes amyloid beta protein i.e they are now deposit which can not be dissolved by protease nor be repaired. Finally they change the architecture of the cell and physical function of cell where they live. This leads to neurodegeneration.

Pathophysiology of Alzheimers diseasePathology: extracellular neuritic plaque, intracellular tangles, neuronal lossCompensatory astrocytosis occurs and microglia proliferation also occurs.Neurofibrillary tangles are paired helical filaments composed of hyperphosphorylate form of microtubules associated protein tau.

Brain aging related factorsInhibits protein phosphatesActivate protein kinase- AAbnormal Glycation, nitration, amination, ubiquitationOf TauTau cant be dephosphorylatedPhosphorylation of tauHyper Phosphorylation of tauPhosphorylated Tau invade or sequestrate in normal tauCytoskeleton wont be stabilized [ function of Tau is lost ], due to synuclein involvement for neurofibrillary tangles, the axonal transport is affected [ function of synuclein is lost]This abnormal tau cannot be dissolved by protease, ubiquitin nor can be repaired by chaperoneNeurodegeneration

Amyloid beta proteinGenetical mutation of Amyloid precursor protein gene [ primary role of this protein is not known, as they are the precursor of amyloid beta protein, they are named as APP]The mutated gene produce mutated protein so, these APP can not be dissolved by proteolytic enzymes like [ beta amyloid precursor protein cleaving enzyme]Genetical mutation of PS1 gene that produce the protein presenelin. Presenelin is gamma secretase protease complex that is responsible for proteolysisMutated presenelin means mutated ProteaseThis mutated protease cannot cleave the protein like Amyloid beta protein.More the amyloid beta protein deposition in cell [ agregated amyloid beta protein]Neuro inflammation [ microglia activation], neuritic injury, neurodegeneration

Foot notesBy tectonic fold and volcano, hills are formed ..by thickening of cells tectum is formed.A plastic when heated it folds, disintegrate into drops or aggregate to form a compact mass..this is denaturation of polythenesame way when protein gets heated or change in buffer they denatures.HSP, chaperone unfolds the misfolded proteins.Ubiquitin : if knot of shoe lace is very tight , it has no choice beside cuttingso if protein cannot be unfolded by HSP, they are dissolved by protease by the help of ubiquitin.Cytoskeleton is the frame of cell which maintains the structural integrity of cell, while tau protein are responsible for binding cytoskeleton into its positon.*cohort study 2006/2007 batch CTGU*

cohort study 2006/2007 batch CTGU

Questions that may be expected for examinationDefine tegmentum, substantia nigraDefine cistern and name them.Define reticular formation and parts of reticular formation.Define or mention the function of cytoskeleton, tau protein, amyloid protein, tangles, lewy body, chaperone and heatshock protein.What are the function of synuclein?Describe shortly the process of release of neurotransmitter vesicles.Illustrate the pathophysiology of Parkinson diseaseIllustrate the pathophysiology of Alzheimer's disease.Draw and name the parts of brainstem.Illustrate Autonomic nervous system.*cohort study 2006/2007 batch CTGU*

cohort study 2006/2007 batch CTGU

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