WEEK 4: Neurodegenerative Disorders Flashcards
General term for loss of memory and other mental abilities
severe enough to interfere with daily life; caused by physical
changes in the brain.
DEMENTIA
____________ considered the most
common cause of dementia worldwide (60%) and ________________ as the second commonest (30%).
AD, vascular dementia
the pathology of this is simply patients
having multiple or accumulated micro infarcts in different
parts of the brain that have been asymptomatic.
Vascular Dementia
main gross pathology here is atrophy of the brain. Simply
meaning that lot of neurons become dysfunctional, perceived
to be of no use and undergoes death through apoptosis.`
Dementia
The pathology associated with Alzheimer’s are of two lesions:
amyloid plaques and neurofibrillary tangles also known as tau tangles
mild cognitive impairment: where is the lesion?
Medial temporal lobe
Mild AD where is the lesion?
The dse spreads to lateral temporal and parietal lobes
Moderate AD where is the lesion?
Dse spreads to the frontal lobe
Severe AD where is the lesion?
Disease spreads to the occipital lobe
• Age related disease
• Progressive neurodegenerative disorder characterized by
cognitive decline and the presence of two core pathologies:
amyloid plaques and neurofibrillary tangles.
• Presence of a sustained immune response (chronic
inflammation) in the brain has emerged as a third core
pathology.
AD
Amyloid plaques vs neurofibrillary tangles?
Amyloid plaques accumulate outside the neurons
between the axonal connections but will eventually
interfere with the transmission of neuron signals.
Neurofibrillary tangles accumulate within the cytoplasm of
the neurons and cause a total dysfunction of the neuron.
• Integral membrane protein expressed in many tissues and
concentrated in the synapses of neurons
• Its primary function is not known
• Implicated as a regulator of synapse formation, neural
plasticity, antimicrobial activity, and iron export.`
Amyloid precursor protein (APP)
is the capacity of the brain to develop
complex neuronal connections. Transmission of neuron
signals is not linear; it’s circular.
Neural plasticity
critical initiator that triggers the progression of Alzheimer’s Disease
amyloid B peptide
T or F? The degree of clinical manifestation will depend on how much of the B amyloid has accumulated at synaptic junctions and the number of synaptic junctions affected
T
T or F AB peptide is a physiologic product,
T
Because of the chronic inflammation going on in the brain, microglial cells become dysfunctional. They now cannot remove the normal Ab amyloid physiologically produced T or F?
T
how does Amyloid B peptide accumulate?
- Caused by A overproduction or perturbation clearance or both
- A generated from amyloid precursor protein through sequential cleavage of and -secretases
- A removal is dependent on the proteolysis, lysosome degradation system and glial cells.
In a state of chronic inflammation, there is an over production of amyloid. Normal glial cells will be over exhausted and gradually become dysfunctional. To or F?
T
Chronically activated microglia release a variety of pro-inflammatory and toxic products, including
reactive oxygen species, nitric oxide, and cytokines
is the protein that is formed in the neurofibrillary tangle, but it is also a normal protein that we all have in our brain.
Tau
where is tau most abundant?
• It is most present in the axon of a neuron. In the axon, it is attached to the microtubules.
What is the major cytoskeleton of the neuron?
Microtubules
Neurofibrillary tangles are formed by ?
hyperphosphorylation of the tau protein, causing it to aggregate, or group, in an insoluble form.
______makes the neuron dysfunctional as its microtubules have become disorganized. Components of the neurons cannot communicate with one another to generate an electrical signal which is the ultimate function of a neuron.
misfolding
The formation of tangles is an important component of AD, and the increased tangle burden in the brain over the course of the illness eventually appears to become independent of the Aβ. To ro F?
T
a cell that is rendered dysfunctional and of no use to the function of the tissue which it is a part of will be
triggered to undergo apoptosis
What is the mechanism of cell death in AD?
Apoptosis
in the normal physiologic fxn of the cell free radicals are formed and these free radicals are constantly removed by the antioxidants that are also simultaneously produced in the cell. T or F?
T
they can phagocytose amyloid-β (Aβ) and secrete pro-inflammatory cytokines that influence the surrounding brain tissue.
Microglia
a general term describing problems with reasoning, planning, judgment, memory and other thought processes caused by brain damage from impaired blood flow to your brain.
Vascular dementia
What is the basic pathology in vascular dementia?
Ssmall cortical infarcts
Characterized by progressive loss of neurons in fxnally related areas of the CNS
• Characterized by neuronal death, neuronophagia, reactive fibrillary gliosis
Neurodegenerative diseases
is a neurodegenerative disease characterized by progressive degeneration of upper (UMN) and lower (LMN) motor neurons in the brain and spinal cord.
ALS
Amyotrophic lateral sclerosis is aka?
Lou Gehrig’s disease, or Charcot disease
What is the most common pathology that triggers death of the neuron?
axonal dyscfunction
are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells
Glutamate receptors
Pathways that lead to cell death in ALS may be mediated by the following:
o Oxidative damage o Mitochondrial dysfxn o Caspase-mediated cell death (apoptosis) o Defects in axonal transport o Abnormal growth factor expression o Glial cell pathology o Glutamate excitotoxicity o Aggregation of abnormal protei
a slow, progressive, neurodegenerative disease of the extrapyramidal motor system.
PD
_________ in the substantia nigra are primarily affected, and degeneration of these neurons causes a disruption in the ability to generate body movements.
Dopamine Neurons
a part of the midbrain the connects the cerebrum with the cerebellum.
Cerebral peduncles
functions of basal ganglia?
control complex patterns of motor activity;
Cognitive control of motor activity;
To change the timing and to scale the intensity of movements
o a pigmented layer of gray matter (extrapyramidal system)
o contains nerve cells with melanin pigments
o dorsal compact part & ventral reticular parts
o afferent fibers – motor cortex, corpus striatum
o efferent fibres – spinal cord & red nucleus
o fxn – control of muscle tone
substantia nigra
What is the chemical that is essential to the fxn of substantia nigra?
Dopamine
what’s the disease?
Presence of Lewy bodies and the loss of dopaminergic neurons in the substantia nigra pars compacta
PD
eosinophilic inclusions containing a loosely compacted core of aggregrated ⍺-synuclein (synaptic protein) and other proteins
Lewy bodies
pahtogenesis of Lewy bodies:
Mutation in the gene encoding _______ resulting in conformational change in protein structure and fxn
⍺-Synuclein
why does lewy bodies accumulate?
- Widespread mitochondrial dysfxn is very closely
2. The impairment of protein degradation pathways
What are 2 protein degradation pathways?
▪ Ubiquitin-proteasome system
▪ Autophagy-lysosome pathway
protein complexes which degrade unneeded or damaged proteins by proteolysis; a major mechanism regulating the concentration of certain proteins and degrade misfolded proteins.
Proteasomes
Proteins are tagged for degradation with small protein called ___________
ubiquitin.
4 cardinal signs of PD?
TRAP: Tremor, Rigidity, Akinesia, Postural Imbalance
