Chapter 15 BB

Alziemer’s is a form of

the stages

diagnosis

what causes Alziemr’s antamocally

dementia that is eventually fatal

early, mild, moderate, severe

asks questions to see if coordinated

amyloid beta starts chain reaction that ultimately causes Alzeimer’s

parkins son’s symptoms

caused by what anatomically

dianosis

treatment

slow movement, skaking in hands, arms, poor coordinaiton, later cognintnive decline

caused by loss of dopamine producing cell neurons in the substantia nigra-a midbrain structure part of basal ganglia

no definitive test, only neurological tests and medical history

• treatment with lerodopa relieves symptoms, not cures, and prolonged use can cause dyskinesia, abnormal uncontrolled involuntary movement.

• DBS is used for those who don’t respond to medication, which interferes with signals that cause motor problems of Parkinson’s

ALS: what is it

symptoms

causes

treatment

group of progressive, ultimately fatal motor neurons diseases

muscle weakness, eventual paralysis in hands and feet

motor neurons degenerate and die

• edavamore(inhibits production of cell damaging free radicals)

• riluzone(decreases glutamate levels) are treatments

Huntington’s: symptoms generally

caused (anatomically)

symptom progression

what mutation appears, how many times

treatment

heritable impairs voluntary movement and cognition

caused by mutations to the HTT gene, codes for Huntington protien in chromosome 4

1. begins w/ depression, chorea, moodswings

2. chorea worsens, cognitive worsens, voluntary actions worsen

3. leads to seizures

disease mutation has CAG sequence repeat 36-120 times in mutation, but 10-35 is normal

• more number of times, the earlier symptoms appear

• basal ganglia and cortex are most affected.

• deutetrabenazine fortreating chorea associated w huntington’s

neurodegenerative diseases all involve a progressive___

destruction of nerve cells.

there is a theory that neurodegenerative dis-eases involve misfolded proteins called

prions

in the case of prions, what happens to the protein?

a protein’s normal 3-D structure has somehow been altered, so that it no longer functions correctly.

alzheimer’s early and mild stage symptoms

early: memory, concentration problems, disorientaion

mild: personality/behavior changes, wandering, losing items

alzheimer’s moderate and severe stage symptoms

moderate: trouble recogining family, difficulty getting dressed, can’t learn new things

severe: completely dependent on others for care. groans for communication, sleeping increases, bedridden

In Alzheimer’s, amyloid-beta forms ___ plaques, also known as ____ plaques.

extracellular senile plaques, also known as neuritic plaques

two biomarkers for Alzheimer’s

amyloid beta, tau

what is wrong with the plaques that amyloid beta forms?

These malformed clumps contain a fragment of the preliminary protein

what does tau protiens do in alzheimer’s, and what does it typically do

tau, a type of protein that normally stabilizes the cellular skeleton, forms neurofibrillary tangles inside neurons.

why is neuroimaging used in Alzheiner’s disease and how does it work

uses a mildly radio-active chemical marker that binds to amyloid plaques and shows their location in PET scans of living people.

Those with CTE show a buildup of what protien in brain cells

tau protien

what shows damage in Alzheimer’s early?

neuronal transport system

In Alzheimer’s disease, and __ are damaged and ultimate-ly destroyed.

axons and synapses

what is amyloid beta formed from?

malformed clumps of a fragment of amyloid precursor protein (APP), a fibrous protein often found at neuronal synapses

describe how amyloid beta intimates the erosion of synapess

In its soluble form, amy-loid-beta can bind strongly to neural receptors, which initiates the erosion of synapses

difference between soluble and insoluble form of amyloid beta

soluble form is highly synaptotox-ic, while the insoluble form (which has low toxicity) tends to aggregate, and is found in much higher concentrations than the soluble form. Some research suggests that the highly toxic, soluble form would be a better target for effective therapie

amyloid beta accumulations first appear in

the neo cortex

what is amyloid beta’s neurotixity bc of

be due to the fact that it exacerbates oxidative stress and damages the mitochondria, the cell’s primary energy supply unit, initiating a cascade of neuronal dys-function and cell death.

formation of neuritic plaques induces

s tau pro-teins to become defective and tangle into neurotoxic neurofibrillary tangles (hyperphosphorylated tau protein) within neuron cell bodies.

what does normal tau protein do

normal tau protein stabilizes micro-tubules, which are crucial to axonal transport

where are neurofibrillary tanges first seen

entorhinal cortex and hippocampus- regions responsible for short-term memory and for transferring those memories to longer-term memory.

Even before it aggregates, malfunction-ing tau can damage cellular transpor-tation by

blocking the microtubule tracks.

Plaques and tangles are known to negatively interact with _______, non-neural brain cells that act as immune cells for the central nervous system, and _____, which offer physiological regulation and structural support in the brain

microglia, astroglia

Dominant mutations in WHAT three genes —_______ — cause early-onset familial Alzhei-mer’s disease that starts when people are in their 40s and 50s?

APP, PSEN1, and PSEN2

in late onset Alzheimer’s the variant of what gene is a major genetic risk??????

APOE, Apolipoprotein E

the normal ApoE is produced by_____-and helps clear_____ from the brain

y astroglia or damaged neurons and helps clear soluble amyloid-beta from the brain.

Two large programs are currently studying early onset Alz. name them

The Dominantly Inherited Alzheimer Network

Alzheimer’s Prevention Initiative

What gene, which codes for a protein responsible for moving proteins into mitochondria, has a complex relationship with Alzhei-mer’s?

TOMM40 gene

how many prescription drugs are approved by FDA for Alzheimer’s

five

three of the prescription drugs for Alz are classified as

cholinesterase inhibitors:

what do cholinesterase inhibitors do

Cholinesterase inhibitors stop the action of acetylcholinesterase, an enzyme that breaks down the neu-rotransmitter acetylcholine.

Effect: This increases the available amount of acetylcholine (involved in learning and memory), which counteracts the damaging effect of the disease on production of this neurotransmitt

the fourth drug for Alz is classified as a

NMDA receptor antagonist

In Alzheimer’s, the damaged cells become overwhelmed with calcium, further damaging the neurons — a condition called what?

neuronal excitotocicity

what does memantine do?

Memantine blocks the flow of calcium through NMDA- receptor channels.

fifth medication for Alz combines ____

The fifth approved medication combines donepezil and memantine.

name what stage that each of the drugs can be taken

Donepezil can be used in all stages of the disease,

galantamine for mild to moderate stages,

memantine for mod-erate to severe stages, and

rivastigmine in all stages.

The donepezil/memantine cocktail is used to treat moderate to severe Alzheimer’s.

active vs passive immunization

active immunization (which trains the immune system to build a person’s antibodies) and passive immunization (which transfers already active defen-sive antibodies without bolstering the person’s own immune system)

what is the second most common neurodegenerative dis-order in humans

Parksinson’s

Parkinson’s is more prevalent in men or women?

men

parksinson’s is caused by the loss of

dopamine producing cells in the substantia nigra, a part of the basal ganglia

Some early onset cases of Parkinson’s are linked to mutations in the ______-gene

PARK2 or PRKN gene

Q: What chemical is used to induce a Parkinson’s disease model in mice?

A: MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

Q: What does MPTP metabolize into in the body?

A: MPP⁺ (1-methyl-4-phenylpyridinium), a neurotoxin

Q: MPTP / MPP⁺ causes degeneration of neurons in what brain region?

A: Substantia nigra

Q: What is one limitation of the MPTP mouse model of Parkinson’s disease?

A: It does not fully replicate human Parkinson’s symptoms, including motor deficits.

What are induced pluripotent stem (iPS) cells?

A: Specialized adult cells (often skin or blood) that are reprogrammed into an embryonic-like, pluripotent state.

Q: What are the two main types of stem cells discussed in Parkinson’s research?

A: Fetal stem cells and induced pluripotent stem (iPS) cells.

Q: In Parkinson’s disease models, transplanted iPS cells can differentiate into what neuron type?

A: Dopaminergic (DA) neurons.

Q: In a 2017 Kyoto University study, human iPS cells transplanted into MPTP-treated monkeys integrated into what brain region?

A: The striatum.

two treatments for ALS

edaravone, riluzole

what does edaravone do

an antioxi-dant that inhibits the production of cell-damaging free radicals, can ameliorate disease symptoms.

what does riluzone do

decreases glutamate levels, and has been shown clinically to extend the life of ALS patients by a few months.

In ALS, the motor neurons degenerate and then die. Without this neural communica-tion, what happens?

a person’s voluntary muscles weak-en, begin twitching, and finally atrophy

familal vs sporadic ALS

ALS cases are due solely due to genetic factors — a condition called “familial ALS

non familial is sporadic

Q: What is the most common genetic mutation associated with familial ALS?

A: C9ORF72

Q: Mutation of which ALS-associated gene can cause both ALS and frontotemporal dementia (FTD)?

A: C9ORF72

Q: Mutation of which gene prevents production of the enzyme superoxide dismutase in ALS?

A: SOD1

there is treatment being curated for ALS patients with what gene mutation

SOD1

Q: What is the inheritance pattern of Huntington’s disease (HD)?

A: Autosomal dominant

Q: If one parent has one copy of the HD variant of the HTT gene, what is the child’s chance of inheriting it?

A: 50%

Q: When does the most common form of Huntington’s disease typically begin?

A: In adulthood, usually in the 30s–40s

Q: How long do patients with adult-onset Huntington’s disease typically live after symptoms begin?

A: About 15–20 years

Q: When does juvenile Huntington’s disease begin?

A: In childhood or adolescence

Q: How long do patients with juvenile Huntington’s disease typically live after symptoms begin?

A: About 10–15 years

symptoms of huntingotns

Signs of HD begin with irritabil-ity, mood swings, depression, small involuntary movements (called cho-rea), poor coordination, and difficulty making decisions and learning new information. As the disease progresses, the chorea becomes more pronounced and patients have increasing trouble with voluntary movements like walk-ing, speaking, and even swallowing. Their cognitive problems also worsen.

specific symptoms for juvenile huntingtons

school performance declines as thinking and reasoning abilities become impaired, and seizures occur in 30 to 50 percent of children with this condition

Huntington’s disease

was found to be caused by mutations

in the HTT gene, which codes for the

___-protien, on chromosome ___

Huntington’s disease

was found to be caused by mutations

in the HTT gene, which codes for the

huntingtin protein, located on chro-

mosome 4.

in huntington’s, the CAG sequence is repeated

36 to 120 or more times in the

mutation. The greater the number of

CAG repeats, the earlier symptoms

appear and the more severe they are.

areas most affected by huntington's are

basal ganglia (volutnary movement) and the cortex

(cognition, perception, and memory).

drdug for treating huntingtons and what of it?

the drug deutetrabenazine for

treating chorea associated with Hun-

tington’s disease.

whats implicated with huntingtons and other neurodegenerative diseases comonly

tau

whats being researched as a biomarker for ALS

neurofilament light chain

what is a gene silencing drug for huntingtons being researched

IONIS-HTTRx is

an antisense oligonucleotide — a

single strand of a chemically modified

DNA designed to interrupt and

decrease the mutated form of the

huntingtin protein produced in HD

patient

______) and _______ are found at elevated levels in cerebro-spinal fluid of HD patient

tau, neurofilament light chain