ap exam 2 AD/Schizophrenia/ anxiety/ stress/depression Flashcards
- Describe the main symptoms of Alzheimer’s disease
- clinical hallmark: progressive impairment in memory, judgment, decision making, and orientation to surroundings, and language
- neurodegeneration in the cortex and hippocampus
- pathological hallmarks: neuronal loss, extracellular senile amyloid plaques, and intracellular neurofibrillary tangles
- definitive diagnosis can only be made by autopsy
- both genetic and sporadic forms
- heritable = familial AD
- unknown cause = sporadic AD
- Describe the senile plaques
amyloid plaques (aka senile plaques)
- largely comprised of a protein called b-amyloid
- small protein (39-42 amino acids, ~4 kDa)
- normal protein, present in biological fluids in a soluble state at low levels
- in AD, b-amyloid self-associates; forms aggregates
- highly insoluble
- deposits extracellularly in the form of plaques
- Describe the neurofibrillary tangles
•Tangles (AKA Neurofibrillary Tangles –NFT)
§Hyperphosphorylated protein Tau causes fiber formations which twist among themselves
•Normal Tau
§Gene found on chromosome 17q21
qMAPT produces via alternative splicing
§Stabilizes microtubules
qBinds to tubulin
qAt distal axon
§Aids axonal transport
qAxon to soma and back
Like light-rail transportation
Genes implicated in Alzheimer disease: APP
most persons with Down’s syndrome develop AD neuropathology by 4th or 5th decade of life
- Ab plaques apparent in young
several different candidate genes considered as cause
- APP gene is located on chromosome 21
- most believe this is the cause of AD in Down’s persons
- evidence that extra copy of APP gene increases
amount of Ab42
- APP gene also harbors mutations that cause early onset FAD
• FAD w/ double mutation in APP at Ab N-terminus
- causes increased levels of Ab to be produced
- suggests high Ab levels can cause AD
• FAD w/ point mutations in APP at Ab C-terminus
- cause relatively more of the longer type of Ab42 (vsAb40)
- suggests that altering type of Ab can cause AD
- Describe the genes implicated in Alzheimer’s disease
Genes implicated in Alzheimer disease: presenilins
presenilins function as part of the gamma- secretase enzyme that determines C-terminal length of Ab
- presenilin mutations are the most common causes of FAD (70% in PS1 and 20% in PS2)
- persons with presenilin mutations show high levels Ab42 in brains
-more likely to aggregate
- Describe the role of apolipoprotein E alleles in AD
- apolipoprotein E (apoE)
- not a mutation, but a risk factor
- three normal alleles : e2(10%), e3(75%), e4(15%)
- allele e4 associated with increased risk of late-onset AD
- allele e2 associated with reduced risk
- apoE is involved with lipid transport; the e4 allele is associated with hypercholesterolemia
- apoE may be involved in clearance of Ab
- apoE e4 may have poor function than other isoforms
• Can baptists and Tauists work together?
all genetic links to AD implicate b-amyloid as cause of AD
- presenilin mutations increase total Ab, and ratio of bad Ab: good Ab (longer 42 aa. form; aggregates more)
- apoE involved in Ab clearance, may affect aggregation
- chromosome 21 changes increase total Ab levels
- Describe the role of acetylcholine transmission in AD
- acetylcholine signaling important for learning & memory and it is affected early in AD
- therefore increase ACh signaling as treatment strategy to partially restore/improve neural function
- acetylcholinesterase (ACh-E) inhibitors include
Aricept (aka donepezil),
Cognex (aka tacrine),
Exelon (rivastigmine),
Reminyl (galanthamine)
- Describe the role of excitatoxicity in neurodegenerative diseases such as AD
newest FDA-approved medication for AD
- Namenda (aka memantine)
- memantine has low - moderate affinity for NMDA subtype of glutamate receptor
- over-activation of NMDA receptors causes excessive excitability in neurons that can lead to cell death
- called excitotoxicity
- excitotoxicity thought to contribute to neurodegenerationin AD
Agonist:glutamate, NMDA
Coagonist: glycin, D-serine
Antagonist: AP5, 5-7 di-CL-KYN
- Describe the three phases of stress response
- Hans Selye: threatàthree stage response
- The Stress Response and the General Adaptation Syndrome
§Phase 1 – Alarm response (sympathetic arousal)
§Phase 2 – Resistance (mobilized coping and action)
§Phase 3 – Exhaustion (chronic stress, permanent damage)
- Describe the HPA axis and the hormones
§Neuroendocrine system
§Catecholamines and glucocorticoids
- Adrenal-medullary system
- Epinephrine
- Hypothalamic-pituitary-adrenal axis (HPA)
- Cortisol
•Function of the Hippocampus in HPA-Stress Response Cycle
§Hippocampus – Limbic system, responsive to cortisol
§Hippocampus helps to turn off the HPA cycle
§Chronic stress may damage cells in the hippocampus
§Hippocampal cell damage can keep the HPA loop going
HPA axis cycle throughout the body
- stress starts in the hypothalamus
- corticotropin releasing factor (CRF)
- Pituitary gland
- Adrenocoorticotropic hormone (ACTH)
- to adrenal cortex
- secreation of cortisol increases energy from storage and regulates immune system
Adrenal mudullary system
- autonomic nervous system (sympathetic division)
- adrenal medulla
- secreation of norepinephrine (increase heart rate, increase respiration, raise blood pressure)
- Describe how amygdala and hippocampus regulate HPA axis
Regulation of the HPA Axis by the Amygdala and Hippocampus
§Both regulate CRF neurons
- Amygdala projects to bed nucleus of the striaterminalis, which activates the HPA axis
- Hippocampus deactivates the HPA axis
ØGlucocorticoid receptors
ØFeedback loop
§Push-pull style regulation
- Describe the relationship between stress, NE and anxiety
•Stress and the brain
§Cortisol has a profound effect on the hippocampus which is critical in memory formation
- Impacts the size of hippocampal dendrites, as well as adult neurogenesis in the hippocampus
- Effective coping also influences hippocampal changes
stress and the brain
glucoccorticoids increase
BDNF decrease
atrophy and decreased survival
increased vulnerability
- Describe the limbic systems (components and function)
•The Papez Circuit
§Described by James Papez (1937)
§Interconnected limbic structures, including cingulate gyrus, hippocampus and hypothalamusthat are involved in emotion, short-term memory and automatic functions. It links conscious functions of cerebral cortex with autonomic functions of brain stem.
§Overtime, the concept is expanded to include other structures such as amygdala.
Structural Components of the Limbic System
•Limbic lobe of cerebral hemisphere:
–cingulate gyrus - plays a role in expressing emotions via gestures, and resolves mental conflict
–hippocampus - converts short-term memory to long-term memory…memories charged w/ emotion are often retained
•Fornix: tract of white matter
–connects hippocampus with hypothalamus
•Anterior nucleus of the thalamus:
–relays information from mamillary body (in hypothalamus) to cingulate gyrus
•Amygdala: deals with anger, danger, and fear responses
–interfaces limbic system, cerebrum, and sensory systems
•Reticular formation:
–stimulation or inhibition affects emotions (rage, fear, pain, sexual arousal, pleasure)
•The Heinrich Klüver-Paul Bucy Syndrome
-Temporal lobectomy in rhesus monkeys
qDecreased fear and anger
qDecreased vocalizations and facial expressions
-Temporal lobectomy in humans
qExhibit symptoms of Klüver-Bucy syndrome
qFlattened emotions
-Probably related to destruction of the amygdala
•The Amygdala and Fear
•The Amygdala and Fear
§Bilateral amygdalectomy reduces fear and aggression in all animals tested
§Anger, sadness, and disgust may also be affected
§Electrical stimulation of amygdala -> Increased vigilance or attention
§Fearful faces produce greater amygdala activity than happy/neutral faces
