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Physiology of Aging - Lecture 8
Terms in this set (79)
General model for Alzheimer's
amyloid-beta and APOE4 interact with age, tau, risk factors (like head injuries,cardiovascular disease, diabetes,and inflammation) to produce neuron degeneration and cognitive deficits
specific model for Alzheimer's
anyloid-beta may aggregate and accumulate in the brain due to its increased production, decreased degradation, or reduced clearance across the blood-brain barrier. Oligomers of amyloid-beta inhibit synaptic functions an dneuronal signaling, and trigger the release of neurotoxins from glial cells. neuritic plaques displace and distort neuronal processes. APOE4 impairs amyloid-beta clearance and promotes its deposition. When neurons are stressed, APOE4 is cleaved, much more than APOE3, into neurotoxic fragments that disrupt the cytoskeleton and impair mitochondrial functions. The cytoskeletal protein, Tau, is normally abundant in axons, but becomes mislocalized to the neuronal cell body and dendrites and forms inclusions called neurofibrillary tangles. a-synuclein can also self-assemble into pathogenic oligomers and form larger aggregates, Lewy bodies. Both tau and a-synuclein can also be released into the extracellular space and may spread to other cells. Vascular disease imparis nutrient supply and waste removal, promotes the activation of glial cells, and can produce micro-infarcts.
cure for alzheimer's
there is no known cure for alzheimer's, but patients may be treated to attenuate the systems of alzheimer's
(1) Acetylcholinesterase inhibitors (ex: Aricept)
(2) NMDA receptor antagonist (ex: Nemenda)
these increase the available acetylcholine in the brain, preventing thedegradation of acetylcholine. This treatment may lessen symptoms of the disease, but does not stop the progression.
NMDA receptor antagonist
this inhibits the activation of this glutamate receptor, which can decrease abnormal neuronal activity in an alzheimer's brain. It may help the patient to think more clearly, but it does not stop the disease
the activation of glutamate receptros can lead to..
overactivity in the brain, which causes disorganized thoughts.
Preventative measures against Alzheier's
there are several types of drugs that have been associated with a decreased incidence of alzheimer's. they lower the risk of the disease and provide clues to the molecular pathology of it. there is still no definitive evidence that any of these measures will prevent alzheimer's in an individual.
specific preventative measures recommended to prevent alzheimer's
a healthy low-fat diet that is high in antioxidants, fruits, vegetables, and fish, regular exercise, continuous social and mental stimulation, high level of education, and control of cardiovascular risk factors. There is no definitive evidence, however, that these measures are effective in an individual, especially those who are predisposed to the disease.
(1) NSAIDs (non-steroidal anti-inflammatoory drugs, like ibuprofen)
(2) cholesterol lowering drugs (statins, like Lipitor and Zocor)
these drugs lower the risk of contracting alzheimer's. They may alter gamma-secretase activity, causing cleavage of APP at a different site. Gamma-secretase produces a 38 aa product instead of a 42 aa product. These drugs decrease inflammation, which is thought to be involved in the progression of alzheimer's disease
have 3 actions that could be responsible for lowering the risk of Alzheimer's:
(1) statins inhibit the Rho/ROCK1 pathway
(2) statins prevent the inflammatory action of immune cells
(3) statins reduce total cholesterol
this pathway promotes cleavage of APP to amyloid-beta42
effects of the inflammatory action of immune cells
amyloid-beta deposits have been shown to increase immunce cell (microglia, monocytes) action, which includes the release of cytokines, ROS, and RNS, which can kill neurons.
primary action of statins
to prevent cholesterol synthesis in the liver. This also allows it to prevent the formation of cholesterol synthesis intermediates, known as isoprenoids.
activate the Rho/ROCK1 pathway and inflammation. Statins therefore inhibit isoprenoids, which decreases inflammation
cholesterol in the neural membrane
the a mount of cholesterol in the neural cell membrane may affect APP cleavage
are drugs that inhibit cholesterol transport from themembrane to intacellular stores. They inhibit amyloid-beta formation in a mouse model of Alzheimer's and also increase memory.
Cholesterol metabolism and alzheimer's
the effect of cholesterol metabolism on alzheimer's is supported by the APOE connection
a lipoprotein found on cholesterol transport molecules (chylomicrons, IDL), which transport cholesterol in the blood and helps in cholesterol metabolism.
Experimental Treatments for Alzheimer's
(1) Antidepressants, like Rolipram
(2) Green Tea
(3) Curcumin (yellow pigment in curry)
(4) Many other drugs still in stages of clinical trials
a phosphodiesterase 4 (PDE4) inhibitor, which prevents degradation of cAMP
is involved in long term memory
cAMP --> PKA --> CREB
amyloid-beta42 suppresses cAMP pathway
is a transcription factor that controls gene expression involved in long-term memory
Rolipram has been shown to:
(1) prevent suppression of cAMP by amyloid-beta-42
(2) increase memory in mice with alzheimer's, but it does not alter amyloid-beta32 deposits
it might be an effective way to improve memory in people with alzheimer's, especially because it seems to work better in old mice than young mice
(1) inhibits acetylcholinesterase and other enzymes that break down acetylcholine
(2) inhibits beta-secretase
(3) it is currently unknown which components of green tea cause these effects, though it is known that it is not caffeine, theophylline, or theobromine
(1) crosses the blood brain barrier
(2) has antioxidant properties
(3) inhibits amyloid beta fibril and oligomer formation in vitro
(4) breaks up amyloid-beta plaques in the brain of aged mice, so it may be an effective treatment for alzheimer's, even after the plaques are formed
(5) is currently being used in clinical trials testings for its use in humans with alzheimer's
Other drugs in clinical trials
many other drugs are in various stages of clinical trials, including agents that target amyloid beta, hyperphosphorylated tau, and APOE4 and insulin delivery to the brain to inmprove glucose uptake. Some of these trails hae been disappointing due to severe side effects, or ineffectiveness, of the drugs.
the second leading cause of dementia; localized loss of neurons
the localized loss of neurons in multi-infarct dementia is due to:
(1) vascular lesions, blood clots (atherosclerosis)
(2) brain hemorrhage (stroke)
is a common cause of multi-infarct dementia that can occur in brain or heart, leading to heart attack, causing a decreased blood flow to the brain
brain hemorrhage (stroke)
causes leakage of blood into the brain, and then neuron death
Infarcts can be detected with...
CT scan, MRI, PET scans.
If infarcts are too small tobe seen with imaging, they can be diagnosed by:
(1) a history of abrupt onset or step-wise deterioration related to transient ischemic attacks
(2) the presence of symptoms of cardiovascular disease, like hypertension and arrhythmmias.
(3) the presence of focal (localized) neurological signs and symptoms
artherosclerosis results in...
plaques and scars in blood vessels that can block blood flow or rupture and produce a blood clot that blocks blood flow
when blood flow is blocked...
the tissue supplied by the blood flow can die, and is called an infarct
multiple infarct senile dementia is..
a dementia produced by multiple focal regions in the brain that have infarcted as a result of injured blood vessels and loss of blood flow.
loss of blood flow causes...
ischemia (insufficient oxygen) and hypoglycemia (low glucose), which can lead to neuronal cells death (though glial cells are more resistant), increased excitatory neurotransmitter release (glutamate), which can promote cel death and cause damage to the blood brain barrier.
ischemia and hypoglycemia can be produced by...
either local occlusion of arteries or global ischemia, which is experienced during a heart attack
how can you prevent multi-infarct dementia?
by decreasing risk of cardiovascular disease (i.e. get cholesterol and blood pressure down)
Motor Control Changes with Aging can be seen in:
(1) Posture and Movement
CNS and posture/movement
cns control of moement is complex, and involves many levels of brain function
three functions of posture/movement:
(1) skilled movements
(2) gross movements and posture
(3) Coordination, adjustment, and smoothing of movements
originate in the motor cortex and form pyramids in the medulla (pyradimal tracts)
requires fine finger control; examples: writing, threading a needle
gross movements and posture
(1) are regulated by the basal ganglia in the midbrain, which is particularly affected by aging
(2) are called extramypramidal tract
Coordination, adjustment and smoothing and movements
(1) controlled by the cerebellum and all of our sensory functions
(2) the cerebellum receives and integrates impulses from sensory receptors (eyes, ears, proprioceptors)
receptors that sense joint position and muscle tension
impulses from "higher centers" control..
spinal and cranial motor nerves. spinal motor nerves travel down the spinal cord, synapse with muscle, and cause contraction of muscle fibers
Posture/movement with aging
(1) skilled motor movements are slowed, but remain well-preserved
(2) gross motor movements are altered, though the degree of alteration depends on the individual
(3) speed of movement can be accelerated or slowed
(4) there can be alterations in the contraction of specific muscles resulting in abnormal movements or posture
alterations in the contractions of specific muscles in the elderly leads to...
a lack of coordination, which causes the high incidence of falls in the elderly
alterations in speed of gross motor movements leads to..
hyperkinesias and/or hypokinesis
accelerated movement, which causes tremors and ticks, characteristic of parkinson's
slowed movement, which leads to freezing, akinesia, etc.
Gait and aging
gait (walking) is typically altered with aging. it becomes more hesitant and broad-based, with smaller steps. these alterations are early signs of Parkinson's. Other changes in gait are stooped posture, diminished arm swinging, and turns that are performed en bloc.
causes of gait and movement changes with age
the causes are not fully understood, though it is known that"
(1) Peripheral changes (like decreased nerve conduction velocity, decreased muscle mass, and increased muscle rigidity) do not account for the alterations in movements, so nerves to muscles are firing perfectly well
(2) CNS impairment is the cause, but it is not well-defined.
(3) movement alterations are more common in females than males. Falls are a common cause of functional deterioration and institutionalization, especially i n women, who may develop osteoporosis and fragile bones after menopause.
Possible preventatives against motor deterioration with aging:
regular exercise throughout life may serve as a protective effect against motor deterioration
evidence for regular exercise as a preventative:
(1) exercise promotes better neurological and mental activity in old age (it improves brain health)
(2) exercise boosts neural cell number (skeletal muscle movement may stimulate new nerve cell growth)
(3) exercise may prevent the loss of nerve cells with dementias (evidence for this has been seen in mice), possibly by boosting nerve growth factors.
(4) regular exercise stimulates the growth of more motor neurons
is a disease of the dopaminergic neurons. Most cell death caused by parkinson's occurs in the substantia nigra.
smooths and coordinates movemens
part of the basal ganglia that controls voluntary movement and helps to regulate mood. The rest of the brain can initially compensate for cell death occurring in this region, it cannot continue to do so when 50-80% of hte cells in the substantia nigra have been lost. once this occurs, other parts of the brain engaged in motor control, including the rest of the basal ganglia, the thalamus, and the cerebral cortex stop working together, causing movement to become disjointed and uncontrollable
present throughout hte brian, though its levels vary from region to region.
Major pathways that are dopaminergic
(1) substantia nigra to striatum
(2) substantia nigra to nucleus accumbens
(3) limbic system
substantia nigra to striatum pathway
is composed of caudate nucleus and putamen. this pathway regulates control of motor function from the cortex, i.e. coordination
substantia nigra to nucleus accumbens pathway
is part of the limbic system. It controls locomotion
regulates emotion and behavior, including sexual and aggressive behavior
regulates endocrine releasing and inhibiting hormones
regulates locomotor activity
dopamine with normal aging
(1) decreases steadily in the corpus striatum, due to dopaminergic cell loss from the substantia nigra
(2) dopaminergic cell loss is probably due to free radical damage, because it is very susceptible to it
(3) this loss may or may not be associated with motor disturbances (usually 50-80% of dopaminergic neuron loss is required before Parkinson's Disease symptoms appear.
Dopamine in Parkinson's Disease
(1) there is severe loss of dopaminergic neurons, most of which occurs in the substantia nigra
(2) this loss is associated with motor disturbances, which can include rigidity and tremor at rest, akinesia (loss of motor function), or bradykinesia (slowed movement), stooped posture, and en bloc turning
(3) dopaminergic neurons projecting to the caudate nucleus and putam (these are both part of the striatum in the basal ganglia) degenerate due to decreased stimulation from substantia nigra. This enhances stimulatory pathways from these regions, back to the substantia nigra
occurs when an individual thinks of a movement they want to do, but are unable to complete it. they have no control over their movements.
Who does parkinson's effect?
it is a progressive disease of the elderly; 1% are affected at age 65, and 5% are affected at age 85+
damage to the substantia nigra leads to...
loss of neurons, gliosis, and the accumulation of Lewy bodies. There is a stroong correlation between lewy body accumulation and the severity of the disease
abnormal intracellular deposits that contain alpha-synuclein and ubiquiting proteins; abnormal proteins clustered together
Parkinson's and Alzheimer's
there is some overlap between the two. Those with Parkinson's have histological changes in the brain that look more like Alzheimer's changes than changes seen in age-matched normals. Alzheimer's patients will often have lewy bodies, which is considered a hallmark of Parkinson's
Parkinson's disease can be induced by...
certain drugs. The chemical MPTP, which is a contaminant in illegal heroine, produce motor deficits, neuron damage patterns, and lewy body formation in animals that is basically identical to Parkinson's disease. MPTP causes mitochondrial dysfunction, which is considered to be a key mechanism for parkinson's disease
advanced features of Parkinson's:
decreased memory, dementia, and postural instability
Genetics of Parkinson's
many genes found to be linked to P.D. are responsible for the early onset and juvenile forms of the disease. 10% of those with P.D. have one of these single gneetic mutations, and none of the genes associated with typical late-onset forms of P.D. have been studied enough to merit diagnostic screenings of these gene variants
table of genes on the last page of lecture notes!
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