Autonomic Nervous System

Physiology ANS vs Endocrine Involuntary Neuroanatomy Somatic nervous system: afferent & efferent Autonomic nervous system: o Afferents from blood vessels ], heart and organs in body cavity o Efferents to smooth muscle, glands, cardiac muscle o Components Sympathetic nervous system Parasympathetic nervous system Enteric nervous system

Viscerosensory System Visceral Afferent Pathway:

Referred Pain: Noxious stimuli that originate in a visceral structure are perceived as pain arisng from a somatic portion of the body wall Mechanism: convergence of somatic and visceral afferents o to dorsal horn neurons Diagnostic tools Comparison of Somatic and Visceral Motor (SNS, PSNS) Neurons Somatic vs. Autonomic Similarities: o Final common pathway ( motor neuron vs postganglion n.) Differences: o Location o 1 neuron vs 2 neuron chain o motor unit vs Boton en pasons SNS vs. PSNS Similarities: o 2 neuron chain o preganglionic fibers are myelinated , postganglionic fibers are unmyelinated Differences: o Location of preganglionic cell bodies o Location of postganglionic cell bodies o Length of preganglionic and postganglionic fibers

Sympathetic System Thoraco-lumbar system location of preganglionic cell bodies (T1-L2 intermediolateral cell column) Courses of SNS preganglionic fibers Sympathetic ganglia (para vs pre) Adrenal medulla Targets

Horners Syndrome Miosis: constriction of the pupil Ptosis: drooping of the upper eyeid Anhidrosis: diminished or absent sweating Internal Organization of Sympathetic Ganglia Divergence o Axons will innervate multiple Convergence o Receive info from many sources preganglionically and info from the target sources

Parasympathetic System Craniosacral system

Enteric Nervous System Control o Motility of the gut o Pancreas o Gall bladder Two major interconnected plexuses o Myenteric (Auerbachs) Plexus Control gut motility o Submucosal (Meissners) Plexus Control the secretory functions of the gut The ENS is autonomous o Disrupt connection with CNs results in no change in small/large bowels o The esophagus ad stomach is more dependent on the SNS and PSNS Neurotransmission of the ANS Acetylcholine o All SNS and PSNS preganglionic neurons o All PSNS postganglionic neuroeffector junctions o SNS postganglionic terminal innervation of sweat glands Norepinephrine o Most SNS postganglionic neuroeffector junctions

o Exceptions Epinephrine is secreted by the adrenal medulla DA is released by the postganglionic fibers innervating renal vasculature Cholinergic Receptors

Adrenergic Receptors

Reticular Formation
Reticular Formation Neurons Raphe Neurons Large (magnocellular) neurons Small (parvicellular) neurons Lateral Column (Receptor Unit) Small parvicellular neurons Receptor unit o Inputs from Spinoreticular tract Other sensory tracts Higher brain centers Relay to medial column Medial Column (Effector Unit) Large magnocellular neurons Effector unit o Caudal projection Reticulobulbar Reticulospinal tract o Rostral projection Thalamus-cortex Limbic structure Median Column Middle line location Raphe serotonergic neurons Projection o Caudal to spinal cord o Cortex and limbic system o Mesolimbic DA neurons Brainstem Nuclei Nuclei in motor system o Red nucleus o Inferior olivary nucleus o Precerebellar reticular nuclei o PPRF (paraedian pontine reticular formation) Periaqueductal gray

ARAS (Ascending Reticular Activating System)& Behavioral Arousal

Function o Asleep o Awake o Alert o Attending Clinical correlations o Coma o Persistent vegetative state o Anesthetics

Modulation of Pain Sensation Input from spinothalamic (DC-ML & ALS) and trigeminothalamic tracts (VTTT & DTTT) Output o Reticulobulbar tracts o Reticulospinal tracts o Raphespinal tracts Mechanism of pain modulation o PAG projects to raphe 5-HT neurons o At dorsal horn, 5-HT activates inhibitory, enkephalinergic interneurons Regulation of Muscle Movements Neuroanatomy o Reciprocal connections with motor nuclei, cerebellum and motor cortex

Function o Segmental stretch reflex o Muscle tone

Control Eye Movements Horizontal conjugated eye movement PPRF o Receive input from Superior colliculus Vestibular nuclei Frontal eye field

Autonomic Control of Cardiovascular Function Preganglionic neurons not intrinsically active SNS: IML (T-L) o Target Ganglionic neurons that innervate heart and vessel Adrenal medulla o Activation: vasoconstriction and cardiac stimulation o Result: increased arterial pressure and tachycardia PSNS: (nucleus amiguus) o Target: heart via vagus nerve o Activation: cardiac depression o Result: decreased heart rate and BP Sympathetic Premotor Neurons These neurons are intrinsically active Location: rostral ventrolateral medulla (RVLM) Targets: sympathetic preganglionic neurons Activation: excitation of SNS preganglionic neurons Result: increased heart rate and arterial BP Brainstem Inhibitory Center Location: caudal ventrolateral medulla (CVLM) Target: SNS premotor neurons in RVLM Activation: inhibition of RVLM Result: decreased arterial BP and heart rate Function: inhibit spontaneous activity of sympathetic premotor neurons in RVLM Not intrinsically active

Nucleus of Solitary Tract Location: dorsal medulla Target: CVLM and NA Activation: excite CVLM (=inhibit RVLM), excite NA Result: decreased arterial BP and heart rate Function: relay visceral afferent (including input from baroreceptor) to provide tonic inhibition of RVLM and excitation of cardiac vagal neurons Baroreceptor Reflex Circuit

Autonomic Control of Respiration Location: respiratory center overlap the cardiovascular center Targets: SNS preganglionic neurons, PSNS nuclei, motor neurons Activation: decrease in blood pO2 will activate chemoreceptor reflex Result: increased heart rate, vascular tone and respiration Hypothalamus Location: multiple hypothalamic nuclei, including PVN Targets: descending autonomic pathway Activation: o Excitation of SNS o Inhibition of PSNS (vagus) o Suppress baroreflex Function: mobilize cardiovascular reserve in the fight or flight or defense response, therefore executive override of homeostatic mechanisms

Central Autonomic Network (CAN) Location: o Hypothalamus o Insular and medial prefrontal cortex o Extended amygdala o PAG Function: o Coordinate local autonomic reflexes o Coordinate autonomic and somatic motor activity o Provide information on planning and execution Regulation of Homeostasis

Cortex & Cortical Function

Forebrain Controls lower centers o Brain stem o Spinal cord

FOREBRAIN
PROSENCEPHALON

DIENCEPHALON

TELENCEPHALON

Telencephalon Components

TELENCEPHALON
BASAL NUCLEI BASAL GANGLIA RHINENCEPHALON CEREBRAL CORTEX
SMELL BRAIN PALLIUM

Rhinencephalon
RHINENCEPHALON
DEVELOPMENTALLY

PRIMITIVE

CORTICAL
REGIONS

SUBCORTICAL
STRUCTURES

ALLOCORTEX

BASAL FOREBRAIN STRUCTURES

Rhinencephalon Derivatives

BASAL FOREBRAIN STRUCTURES

ANTERIOR PERFORATED SUBSTANCE

N. BASALIS MEYNERT

N. ACCUMBENS V. STRIATUM

SEPTAL N. MED. & LAT.

DIAGONAL BAND BROCA

BED NUCLEUS STRIA TERMINALIS

Cerebral Cortex: Developmentally, Morphologically & Functionally

CEREBRAL CORTEX

ALLOCORTEX NON 6 LAYERED

NEOCORTEX 6 LAYERED

PRIMITIVE

HIGHER FUNCTIONS

SURVIVAL

REASONING

ALLOCORTEX
ARCHICORTEX MAXIMUN 3 LAYERS PALEOCORTEX MAXIMUM 5 LAYERS

LIMBIC LOBE

PARAOLFACTORY AREA

SUBCALLOSAL GYRUS

CINGULATE GYRUS

HIPPOCAMPAL FORMATION

UNCUS PIRIFORM

PARAHIPPOCAMPAL GYRUS

Cerebral Cortex: Neocortex (Isocortex) Parietal, occipital, temporal lobes o Reception and elaboration of conceptual data (by association ytakes into consideration our experiences and compares them to come up with things such as a new novel) Frontal lobes o Complex motor responses o Judgment o Foresight Make judgments or look into future based on past experiences o Mood & behavior Has 6 morphological layers Cortical Histology Cortical Mantle Superficial gray matter (consists mostly of cell bodies) Variable thickness o 1.5-4.5mm o cytoarchitecture 2:1 ratio of glial cells to nerve cells four cell types predominate

Cortical Cell Types

Pyramidal Cells o Most predominant o Axons oriented to deeper layers of cortex o Dendrites oriented to superficial layers o Come in 3 sizes: s 10, m 50, l 100 micrometers = betz cells of motor cortex Granule (Stellate) Cells o Interneurons, usually inhibitory o Small (8 micrometer) star shaped o Short axon & dendrites o Form short association fibers Fusiform Cells o Spindle shaped o Located in the deepest cortical layers o Dendrites oriented toward superficial layers o Axons oriented toward deep cortical layers Horizontal Cells of Cajal o Limited to superficial layer of cortex o Spindle shaped cell body with dendrites at both ends

Laminar Organization of Neocortex Layer I: Molecular Layer o Thin layer near the pia o Large synaptic field o Horizontal cells of Cajal Layer II: External Granular Layer o Granule cells most abundant o Small pyramidal cells that terminate in the deeper layers of cortex Layer III: External Pyramidal Layer o Pyramidal cells (medium to medium large) o Axons from: Commissural (callosal) fibers Cortical association fibers (interact with other areas of the cortex within the same hemisphere) o Important projection layer Layer IV: Internal Granular Layer o Mostly granule cells o Input from specific thalamic nuclei (VPL, VPM) o Communicates with layers V. VI Layer V: Internal Pyramidal Layer o Mostly medium & large Pyramidal (Betz cells) o Cells give rise mostly to projection (corticofugal) fibers Influence lower motor neurons Layer VI: Fusiform Layer o Deepest layer or cortex

o Mostly fusiform cells some pyramidal cells o Corticofugal, Association, & Commissural Connections Functional/Morphological Relationship in Neocortex Homotypical o 6 distinct morphological layers o most prominent in association areas o 75% human neocortex association cortex amount unique to humans Heterotypical o Six ill defined morphological layers o Phylogenetically early cortical areas o Seen in primary cortical areas o 25% total human cortex Brodmanns Cytoarchitectural Map: Primary Areas (Heterotypical) Visual (Striate): BA 17 Somatosensory(S-I): BA 3,1,2 Motor (M-I): BA 4 Auditory (Transverse Gyrus of Heshel): BA 41,42 Vestibular: BA 40 Taste (S-II): BA 43 Brodmanns Cytoarchitectural Map: Association Areas (Homotypical) Visual: BA 18,19 Somatosensory: BA 5,7 Motor (M-2): BA 6,8,8a Language (Wernicke): BA 39, 40,22 Motor Speech (Broca): BA 44,45 Prefrontal (Reasoning): BA 9,10,11,12 Cortical Laminar Connections: Overview of Efferent Connections Neurons in deeper layers (V,VI) project to subcortical CNS areas (brainstem, spinal cord, thalamus, basal ganglia) Corticofugal Neurons in layers III & VI project to other cortical areas Cortico- cortical projections o Association Project on same side o Commissural Cross neuraxis (midline) Cortical Laminar Connections: Overview of Afferent Connections Specific Thalamic N. project to a specific cortical layer: IV

Non specific Thalamic N. (CM) project to all cortical layers: I through VI Forebrain & midbrain Subnuclei (N. Basalis of Meynert, Raphe) project to all cortical layers: I through VI Association tracts synapse in layers I & III Callosal fibers synapse in layers I, III & IV

Corticofugal Neurons Cell bodies in layers V & VI form subcortical projections Layer V pyramidal cells project to brainstem (corticobulbar), spinal cord (corticospinal tract)& basal ganglia (corticostriate) Pyramidal cells from layer V of BA 4 form a portion of corona radiata, internal capsule to form the CST Layer VI pyramidal and fusiform cells send axons to thalamus (corticothalamic projections) Cortical Laminar Connections Review Corticofugal Neurons o Subcortical distribution Layer V pyramidal cells Spinal cord (corticospinal) Brainstem (corticobulbar) Basal ganglia (corticostriate) Layer VI pyramidl & fusiform cells Thalamus (corticothalamic) Cortico-Cortical Neurons: Association Axons from layers III & VI synapse in adjacent gyrus or in same hemisphere Cingulum bundle o Interconnects cingulate, parahippocampal g. frontal, parietal, occipital, temporal cortex o Limbic gateway to neocortex Superior Longitudinal Fasciculus (Arcuate Fasciculus) o Interconnects Brocas motor speech area (BA 44,45) with Wernickes sensory speech area (BA 22, 39, 40) o Interconnects frontal, parietal, occipital, and temporal lobes Uncinate Fasciculus o Interconnects anterior temporal area with orbitofrontal cortex o Seizure progression o Uncinate fits Cortical Laminar Connections: Review Corico-cortical Neurons o Association tracts interconnect same hemisphere o Layers III & VI pyramidal cells Cingulum bundle

Superior Longitudinal Fasciculus Uncinate fasciculus

Cortico-cortical Neurons: Commissural Corpus callosum o Interconnects all lobes between hemispheres Genu (forceps minor) interconnects frontal lobes Body interconnects frontal parietal and temporal lobes Does not interconnect hand & foot BA 3,1,2 Splenium (forceps major) occipital lobes Not BA 17 (visual) Anterior commissure o Interconnects inferior temporal gyrus and olfactory cortices Posterior commissure o Pupillary light reflex Cortical Laminar Connections: Review Cortico-cortical Neurons o Commissural neurons interconnect similar gyri in opposite hemispheres o Layers III & VI Corpus Callosum Genu (forceps minor): frontal lobes Body: frontal, parietal, temporal lobes Splenium (forceps major): occipital lobes Anterior Commissure: inferior temporal gyri Posterior Commissure: light reflex Cortical Neurochemistry Glutamate/aspartate & GABA rapid signaling Gluatamate/aspartate Corticofugal, Association, & Commissural fibers o Co-transmitter with neuropeptide GABA Interneurons o GABA alone o GABA + Neuropeptide Neuropeptides o Slow signaling o Peptide only neurons o Co-transmitter w/ Corticofugal and ascending monoamine neurons Transmitters Intrinsic to cerebral cortex o Glutamate/aspartate (projection) o GABA (interneurons) o Neuropeptides (interneurons, projection) Synthetic sources of ACh, NE, DA & histamine is subcortical o ACh N. Basalis (Basal forebrain)

o o o o

NE Locus Ceruleus (Brainstem) 5-HT Raphe (Brainstem) DA Substantia Nigra (A9), VTA (A10) (Mesocortical System) Histamine hypothalamus

Lateralization of Language Dominant hemisphere: controls speech Brocas Area: determines dominant hemisphere Wernickes Area: Language comprehension Handedness vs. Dominance o All right-handed people have left dominant hemisphere o Majority of left-handed people have left dominant hemisphere o Ambidextrous people have mixed dominance Repetition

Info comes in from auditory apparatus and up through the brainstem, through the MGB and to primary auditory cortex (BA 44,42) Then the iformation goes into Wernickes area Then using the Arcuate Fasciculus the information is transferred to Brocas motor speech area to set up the program for what will be spoken Then the info travels to the motor cortex

Reading Aloud

Information comes in from visual system (BA 17) into language comprehension center (BA 18,19) from there it goes to Wernickes area and via the Arcuate fasciculus the info travels to Brocas area; finally it travels to the motor cortex

Hemispheric Asymmetries
COMMISSUROTOMY SPLIT-BRAIN PATIENTS

NON-DOMINANT HEMISPHERE

DOMINANT HEMISPHERE

DOES NOT TALK

PERCEIVES LEARNS REMEMBERS

PERFORMS MOTOR TASKS

LIMITED LANGUAGE COMPREHENSION

SOLVES SPATIAL-PERCEPTUAL PROBLEMS

SPEECH PRODUCTION LANGUAGE COMPRHENSION

ANALYTICAL MATH SKILLS

Cerebral Localization of Cortical Function: Hemispheric Independence Left Hemisphere Right Hemisphere o Intellectual o Perceptive o Rational o Emotional o Verbal o Non-verbal o analytical o Intuitive

Cerebral Localization of Language

Aphasia

o Partial of complete loss of language abilities

APHASIA

BROCA'S (MOTOR) EXPRESSIVE

WERNICKE'S (SENSORY) RECEPTIVE

BRODMANN 44,45

CANNOT SPEAK

BRODMANN 39,40 POST. 22

CANNOT COMPREHEND

Wernickes Aphasia Theory Specific cortical area with UMNs that control & coordinate vocalization muscles = (Brocas) o Face (VII normal) o Tongue (XII normal) o Jaw (V normal) o Throat (normal) Sensory component o Angular gyrus o Auditory &/or visual perception brought to Wernickes area Arcuate Fasciculus o Transfers heard or read word to Brocas Area o Transection of Arcuate fasciculus Loss of ability to speak Conduction aphasia Wernickes : receptive or fluent aphasia o Unable to comprehend spoken words o Unable to read (alexia) o Unable to write (agraphia) o Fluent paraphasic speech (clear, fluent, melodic) but unintelligible (word salad) Agnosia Inability to recognize objects Intact somatosensory system Apraxia Inability to carry out purposeful motor movements Disconnect between planning & execution Absence of paralysis o Intact UMN systems o Intact LMN systems

AGNOSIA

PARIETAL-LOBE LESION

NEGLECT SYNDROME

VISUAL AUDITORY TACTILE

CONTRALATERAL SIDE

LACKS APPRECIATION FOR CONTRALATERAL SIDE OF BODY

CONSTRUCTIONAL APRAXIA

ASSOC. RIGHT HEMISPHERIC LESIONS

Neglect Syndrome Right posterior lobe lesion Lesion of non-dominant hemisphere Neglect of extra-personal space on left side of external world o Constructional (drawing) apraxia o Dressing apraxia Multiple Long Term Memory Systems Declarative Memory (explicit) knowing what; know that Conscious awareness (focus, bring to our attention) Requires hippocampal formation/ medial temporal lobe Non-declarative Memory (implicit) knowing how to independent of conscious awareness Medial Temporal Hippocampal formation not necessary o Habits cortico-striate loops o Sensorimotor cerebellar loops o Emotional amygdala o Priming cortical Memory Short term memory o Limited capacity o No permanent storage Long term memory (Secondary/Tertiary) o Very large capacity o Permanent storage Declarative: through conscious experience Procedural: through conditioning

Sleep
Sleep Stages A normal nights sleep runs in ~90 minute cycles with the proportion of REM sleep increasing during the night The older an individual, the less time is spent sleeping REM sleep declines more with age than non-REM sleep Consciousness and the EEG How do you objectively measure consciousness? Development of the electroencephalogram (EEG) o Hans Berger first recorded mirovolt signals o Summed electrical output of large cortical pyramidal neurons o Large synchronous slow wave EEG = drowsy state o Small, high frequency waves = alert, active subject o Many abnormal firing patterns (e.g epilepsies) can be detected and localized with EEG Until the 1940s the default state of consciousness was assumed to be sleep o Wakefulness was thought to only occur with sensory input o However, sensory input is neither necessary nor sufficient to maintain consciousness Destruction of the pontine and medullary reticular formation results in coma The RF serves as a central pattern generator for o Primitive functions such as respiratory and cardiovascular rhythms o Maintaining wakefulness o Regulating sleep patterns Phenomenological Comparison of the Sleep Cycle States

Sleep Cycle in the EEG Stage 1- falling asleep o Theta waves of low amplitude. Lightest sleep, easy to arouse Stage 2 deeper sleep o More theta waves, but interspersed with rapid sleep spindles Stage 3 deep sleep o Appearance of slow delta waves of high amplitude and low frequency Stage 4 deep sleep (subject difficult to arouse) o Strong delta wave activity o Sleep walking and talking, bedwetting occur in Stage 4 Rapid Eye Movement (REM) Sleep resembles Stage 1 EEG Sleep Cycles: Brain Circuitry

Diurnal rhythmicity originates in the hypothalamus (SCN) Thalamocortical connections regulate NREM sleep ad EEG Midbrain pontine RF regulates NREM-REM cyclic oscillations

Mammalian Clock Genes Regulate Diurnal Rhythms Mammalian clock genes include Per1, Per2, Per3, Cry, Clock, Bmall Genes expressed in ~20,000 SCN neurons Protein products are transcription factors Cyclic, mutual feedback regulates their expression Mutant mice (null) for these genes have disturbed or shifted sleep/wake cycles

REM Sleep: Phenomenology Termed rapid eye movement sleep due to occulomotor activity Most dreaming occurs during REM sleep REM sleep increases following days of new experiences Muscles are relaxed and inactive (termed REM paralysis) REM sleep percentage increases during sleep cycle REM Sleep: Mechanisms Pontine RF is cortical integration site for REM Inhibitory connections to spinal cord reduces muscle tone inhibitory connections to cortex leads to EEG desynchronization most inhibitory connections are aminergic (dopamine, 5-HT) Sleep Disorders Insomnia o Most common sleep disorder o Often related to auxiliary problem (depression, anxiety) o Hypnotics used therapeutically o Current therapies involve agonists for the benzodiazepine site on GABA-A receptor with short half life Sleep apnea o Cessation of breathing during sleep, awakening to begin breathing o Associated wth obesity, compression of the windpipe o Bariatric surgery can assist in resolving sleep apnea Narcolepsy o Excessive sleepiness during the day Sudden breakthrough of REM sleep activating mechanism inyp active, awake domain Cataplexy, loss of motor tone and control o Genetics First discovered in a colony of Doberman Pinchers at Stanford University Mutation in a gene encoding hypocretin Hypocretin null mice exhibit narcolepsy o 90% of human narcoleptics associated with reduced hypocretin (orexin) levels o may be degenerate loss of hypocretin neurons REM Sleep Disorder o Muscles may not become paralyzed as is normal for REM sleep o Subject may consequently physically act out dreams o Different from sleep walking

Night Terrors o Occurs most often during Stage 4 NREM Sleep o Not a nightmare, rather its a panic attack o Subject may remain intensely afraid following arousal Restless Leg Syndrome o Varying intensity involuntary leg movements o A primary cause of insomnia o Linked to several genes, but treated with dopaminergic drugs

The Function of Sleep: NREM In humans, a neurodegenerative disorder (fatal familial insomnia) leads to death after several months Studies have shown that seven hours of sleep correlates with longer life span in humans Striking inverse correlation between sleep time and body mass Though to reflect metabolic repair requirements The Function of Sleep: REM In humans and other mammals, a profound inhibition of motor activity (excepting postural muscles) occurs during REM sleep Destruction of pontine adrenergic neurons removes hibition, leading to thrashing behavior (acting out dreams) Motor inhibition may thus be protective aspect Selective deprivation of REM sleep leads to REM rebound, i.e. more REM sleep REM rebound also follows dugs use (alcohol, LSD, amphetamines) suggesting a need for REM sleep REM sleep appears important for consolidation of short term to long term memory REM Sleep & Memory Although evidence is mounting, if its still a highly debated concept Conflicting data in humans o Dreams in humans do not consistently reflect recent events o REM sleep deprivation does not always alter non-declarative memory o MAO-inhibitors suppress REM sleep, but do not consistently alter memory What are dreams? o Significant but undefined reflections of our experiences

Alzheimers Disease & Dementia I. Introduction AD is the most common from of dementia, a progressive neurodegenerative disease with multiple neurochemical abnormalities AD is also a degenerative metabolic disorder o Rate of energy metabolism is decreased, density of glucose transport sites in microvessels is also diminished Reduction of NT like ACh, 5-HT, NE Neuorpathological features: presence of neuritic plaques & neurofibrillary tangles I several cortical & subcortical areas, hippocampus, basal forebrain including the cholinergic nucleus basalis Genetics Mutations in APP detected in members of AD families Environment, early-life exposure, epigenetic the LEARn (Latent Early-Life Associated Regulation) model Neurobiological Interactions of the key protein molecules: APP, PSI/II, ApoE Amyloid B protein: neurodegeneration B-amyloid precursor protein: neurotic outgrowth, synaptogenesis, developmental role Alpha-antichymotrypisn: neuronal growth BACE: APP processing enzyme Presenilins: protein trafficking The major early hallmark is the deposition of extracellular amyloid Amyloid deposits consist of aggregates of 39 to 43 aa peptide termed as amyloid B peptide (AB) or A4 Various forms of AB Only part of the AB peptide is buried inside the membrane, ~2/3 is extracellular and is inside the membrane AB is an abnormal cleavage of a larger B-amyloid precursor protein (APP) Beta amyloid precursor protein: structure and function APP is an integral type I membrane glycoprotein APP has sites for phosphorlaytion, glycosylation, and sulfation APP is a secretory protein which is secreted in the conditioned medium as a carboxyl truncated form of APP Functions of APP: synapyogenesis, cell adhesion Amyloid Cascade Theory : Processing of APP Generation of AB peptide by abnormal cleavage of APP Amyloid pathway or normal pathway

II. III. IV.

V.

VI.

VII.

 VIII.

o Amyloid pathway sAPPB, AB o Normal pathway sAPPa Role of enzymes: secretase, a secretase, B-secretase (BACE), y-secretase (PSI)

Gene Expression of APP: structure and function of the regulatory protein of the gene APP exists in several distinct foms which are derived by alternative mRNA splicing Encoded on chromosome 21, the gene itself is large The promoter region of APP has a complex transcriptional unit Participation of APOE: different isoforms: E2,E3,E4 a. E4 is a risk factor for AD while E3 acts as a neuroprotective factor b. E4 acts as a chaperone molecule and may participate in B-amyloid formation APP-related proteins: similar to APP but lacking AB domain Treatment strategy: a. Anticholinesterase b. Protease inhibitors (BACE inhibitors) c. Anti-inflammatory drugs d. Anti-oxidants

IX.

X. XI.