Psyc4130 1nd Edition Lecture 28 Outline of Last Lecture I. LTP and the Physiology of Learninga. HCFb. LTPc. What is the physiological basis of learning and memory?d. Hebbs Original Principal e. NMDAf. Ketamineg. Alcoholh. Early LTPi. Late LTPj. Nootropic DrugsOutline of Current Lecture I. Neurodegenerative DisordersII. Alzheimer’sIII. Presentation and ProgressionIV. Brain and Pathology in ADV. Plaques and TanglesVI. Beta Amyloid Plaques VII. Neurofibrillary TanglesVIII. PresenilinIX. Apolipoprotein E (ApoE)X. Aβ-Induced ToxicityXI. Standard RxCurrent 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’so Commonly and know as the “long goodbye”? Alzheimer’s - Demographicso At age 65: 10% of the populationThese 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 forgetfulnesso 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 checkbooko 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 Cortexo Entorhinal Cortex and Hippocampuso 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 Coeruleuso 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 memory-formation circuitry.- Papes circuit?- degrading phenomenon occurring in emotional circuitry in the brain- Late stage alz = ffinally, 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 Plaqueso 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 anddendrites- 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 (Aβ). - Plaques are formed in several steps, beginning with a gene that encodes β-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 Aβ. - In the first step, β-secretase cuts the “tail” off of the APP molecule.- In the second step, γ-secretase cuts the “head” off. - The result of the actions of the secretase is a molecule of Aβ 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 Y-secretase.- 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 Aβ 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 withthe 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 Aβ-Induced Toxicity- It appears that excessive Aβ in the cytoplasm is the cause of neurodegeneration in AD—not the presence of amyloid plaques per se.- Aβ oligomers (i.e. aggregates) activate microglia, triggering the release of toxic cytokines (immune system chemicals that destroy infected cells).- Aβ 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®