Psyc4130 1nd Edition Lecture 28 Outline of Last Lecture I LTP and the Physiology of Learning a HCF b LTP c What is the physiological basis of learning and memory d Hebbs Original Principal e NMDA f Ketamine g Alcohol h Early LTP i Late LTP j Nootropic Drugs Outline of Current Lecture I Neurodegenerative Disorders II Alzheimer s III Presentation and Progression IV Brain and Pathology in AD V Plaques and Tangles VI Beta Amyloid Plaques VII Neurofibrillary Tangles VIII Presenilin IX Apolipoprotein E ApoE X A Induced Toxicity XI Standard Rx Current Lecture Neurodegenerative Disorders Ch 15 Neurodegenerative disorders involve conditions that lead to the progressive and typically irreversible loss of neurons in the brain 1 prevalence Alzheimer s o Commonly and know as the long goodbye Alzheimer s Demographics o At age 65 10 of the population These notes represent a detailed interpretation of the professor s lecture GradeBuddy is best used as a supplement to your own notes not as a substitute o At age 85 of the population Presentation and Progression The first sign is often excessive forgetfulness o Missing appointments failing to remember common words failure to recall peoples names Next a general trend toward increased confusion is observed o Multitasking e g Thanksgiving Dinner o Balancing a checkbook o Memory problems follows anterograde model Know early life stuff can t make new long term memories In the progressed stages the sufferer becomes completely unable to care for himself or herself and ultimately becomes bedridden Average time diagnosis to death 8 years Brain and Pathology in AD AD produces severe degeneration in o Olfactory Cortex o Entorhinal Cortex and Hippocampus o Neocortex especially in the association regions of the frontal and temporal lobes Vast degeneration in major NT systems o Nucleus Basalis ACH Alerting attention memory cognitively vigilant o Locus Coeruleus o Raphe Nuclei The earliest pathologies in the AD are olfactory o i e cant taste food all the way when you are sick The disease then progresses to affect the basal forebrain and the limbic system memoryformation circuitry Papes circuit degrading phenomenon occurring in emotional circuitry in the brain Late stage alz finally neurons are compromised throughout the entire cerebral cortex including regions of association cortex Sulci and fissures are deepened in broadened due to atrophy of neocortex Plaques and Tangles Cytopathology in Alzheimer s reveals two hallmark characteristics of the disease o Beta amyloid Plaques o Neurofibrillary Tangles Beta Amyloid Plaques Extracellular deposits that clump together and stick to the outside of neurons Include a dense core of a protein known as beta amyloid surrounded by dead axons and dendrites Activated microglia and reactive astrocytes are included as well as these mechanisms seek to destroy damaged cells Amyloid plaques are caused by defective beta amyloid proteins A Plaques are formed in several steps beginning with a gene that encodes amyloid precursor protein APP which is comprised of about 700 amino acids APP is then cut in two locations by enzymes known as secreates yielding A In the first step secretase cuts the tail off of the APP molecule In the second step secretase cuts the head off The result of the actions of the secretase is a molecule of A containing either 40 or 42 amino acids This is determined by the second cut Normal brains 90 95 short form AD brains Up to 40 long form High concentrations of the long form tend to fold improperly forming clumps Lower levels can be cleared through ubiquination tagging for destruction by ubiquitin with subsequent transport to proteasomes where they are broken down In AD this system cannot keep up PET scans yellow indicates high uptake of a label that target beta amyloid plaque and red indicates medium uptake Neurofibrillary Tangles These are present inside of the AD affected neurons in contrast with plaques Contain twisted filaments of hyperphosphorylated TAU protein Normal TAU is an important component of microtubules a vital part of the neuron s transport mechanism Analogy twisted railroad tracks cant get a train down it Presenilin Presenilin genes produce presenilin proteins PS1 and PS2 which are subunits of Ysecretase Thus genetic variations in presenilin genes are part of an inherited vulnerability to developing AD Apolipoprotein E ApoE ApoE is a glycoprotein that transports cholesterol in the bloodstream and assists in cellular repair Possessing a certain allele of the apoE gene known E4 enhances risk of late onset AD The purported mechanism is an interference with removing A from outside of neurons E2 allele may confer protection against the development of AD TBI alone is the greatest non genetic risk factor in developing AD but in individuals with the E4 allele this risk is Other risk factors including obesity high blood pressure elevated cholesterol and magnify the risks of AD in people with apoE4 L A Induced Toxicity It appears that excessive A in the cytoplasm is the cause of neurodegeneration in AD not the presence of amyloid plaques per se A oligomers i e aggregates activate microglia triggering the release of toxic cytokines immune system chemicals that destroy infected cells A oligomers also trigger excessive glutamate release by glial cells resulting in excitotoxicity Cells die necrosis apoptosis programmed cell death Standard Rx AChE Inhibitors o Cognex Tacrine o Aricept Donepezil o Exelon Rivastigmine NMDAR Antagonist o Namenda Memantine