Week 10

Question 1

Neuron

Answer 1

1. Highly specialized –> electrical impulses
2. CNS: oligodendrocyte myelination (multiple at once); PNS: Schwann cell myelination (one-to-one surrounded by basal lamina)
   > Insulation, protection, and speeds up transmission of nerve impulse

Question 2

Multiple Sclerosis (no direct inheritance, 20-50)

AUTOIMMUNE (can be genetic from relative or environmental b/c twins are not always affected)

Answer 2

1. Self-immune attacks CNS myelin sheath –> destroys myelin and forms scar tissue (Sclerosis)
2. Exposed fibers and nerves –> slow/blocked transmission of electrical impulse; damaged axon
3. T cells attack with Cytotoxic Factor
4. Astrocytes + macrophages activated: CF secretion, ROS

Question 3

MS Symptoms (dependent on location of affected nerve fibers)

Answer 3

1. Numbness/weakness (one side/LE)
2. Loss of vision/double vision/blurring
3. Electric-shock sensation (head movement)
4. Tremor, fatigue, poor coordination

Question 4

MS Treatment

Answer 4

1. Fingolimod: sphingosine-1 phosphate receptor modulator sequesters lymphocytes
2. Glatiramer: random 4 AA tetramers in myelin basic protein (divert autoimmune response)
3. Natalizumab: anti-VLA4 Ab blocks lymphocytes passing BBB to CNS
   > Normal: capture –> activation –> adhesion strengthening –> transmigration
4. Mitoxantrone: CT drug (block DNA synthesis and kill proliferating IS)
5. Interferon B: reduces disease activity

Question 5

Parkinson Disease

SECOND MOST COMMON NEURODEGENERATIVE DISEASE AFTER AD (onset 50)

Answer 5

1. Diminished substantia nigra –> no signals for body movements going to striatum –> dopaminergic neurons in pathway degenerate (Lewy bodies present in nigral neurons –> abnormal protein aggregates inside nerve cells–ALPHA-SYNUCLEIN)

Question 6

PD Symptoms

Answer 6

1. Tremors
2. Rigidity and stiffness
3. Bradykinesia: movement slowness
4. Hyposmia (reduced smell detection) and postural instability

Question 7

PD Treatment

Answer 7

1. Levodopa: dopamine precursor
2. Carbidopa: dopamine decarboxylase (DDC) inhibitor–delay in conversion of levodopa into dopamine until it reaches brain for sufficient use and replenishment
3. Therapy: deep brain stimulation (DBS): implant sends impulses to disable overactive nerve cells
4. Experimental: iPSCs

Question 8

Huntington’s Disease (HD)

100% pathology in brain
Final Stages 25% brain weight loss

INHERITED AD @ 4p16.3

67 exons, 200 kb of gDNA

Answer 8

1. Combination of granular and filamentous material (INCLUSION BODIES) in affected neuronal nuclei
   > PolyQ –(protease)–> native fragment –> misfolding –> oligomers –(micro-aggregates) –> IB
   > Effects: transcriptional alterations, metabolic dysfunction, proteasome impairment, stress response abnormalities
2. Uninterrupted (40+) CAG/GTC repeats in first exon (CAG –> polyglutamine tract/PolyQ disease/TRED)

Question 9

HD Treatment

Answer 9

1. Huntington in cytoplasm, membranes, and synaptic bulbs (KO mice die before birth)
2. Ionis Treatment:
   > huntington synthesis info locked in DNA –> mRNA carry –> damaged protein created
   > Drug kills mRNA via antisense oligonucleotide

Question 10

Genetic Anticipation
(Sherman Paradox)

Answer 10

1. Unstable TRED –> additional expansions –> LONGER with EARLIER onsets with SEVERE-R SYMPTOMS in sucessive generations (each following generation dies earlier)
2. TRED Expansion –> intrastrand hairpin loop (different DNA replication from each newly synthesized strand; form hairpin structure and creates DNA from same repeating sequence)

Question 11

Fragile X syndrome

(Non-coding Triplet Expansion)

MOST COMMON HEREDITARY FORM OF MR (unusual X-LINKED)

LoF or toxic effect @ mRNA

Answer 11

1. CGG, GCC, GAA, CTG, CAG
   > Repeats (52-200; and 200-1000) in 5’ UTR of F-X mental retardation gene (FMR1) –> CpG hypermethylation at FMR1 Promoter –> low transcription –> less mRNA nucleocytoplasmic shuttling/synaptic protein synthesis (bad regulation)
   > OR point mutation of FMR1 RNA-binding domain and FMR1 deletion

Question 12

Dementia

Answer 12

Cognitive dysfunction in 2+ areas –> significant impairment

> ST memory, communication, focus ability, reasoning, and visual perception

Question 13

Dementia vs Typical Aging

Answer 13

1. ST memory loss vs Forgetfulness
2. Confusion vs Lose track of time
3. Visual/spatial reasoning issue vs vision changes
4. Personality changes vs irritability
5. Struggle to carry out conversations vs can’t think of a word

Question 14

Fronto-Temporal Lobar Degeneration (FTD)

10-15%

Answer 14

1. Pick’s Disease
   > Atrophy in neurons
   > Number one cause in people under 60
   > Spared memory at early stages
   > Progressive decline in behavior, language and motor functions
   > Abnormal protein accumulations and anatomical locations (Tau, TDP-43 and FUS)
   > Tau: Non-fluent Primary progressive aphasia (PPA) with changes in personality and deterioration in speech production
   > TDP-43: Semantic PPA and FTD with ALS with deterioration in word comprehension and motor neurons

Question 15

FTD vs. AD

Answer 15

1. Memory loss at advanced stages vs. early prominence
2. Behavioral change is first symptom vs advanced stages
3. Frequent vs occasional spatial orientation
4. Comprehension vs coming up with word
5. Hallucination is uncommon vs common in advanced stages

Question 16

Dementia with Lewy Bodies (LBD)

10-25%
Risk factors: PD, 50+ REM sleep disorders, family identified with GBA gene

NOT genetic, but AD + LBD SECOND MOST COMMON

Answer 16

1. Sleep disturbances, visual hallucinations, visuopatial impairment, PD like movements
2. Lewy body buildup inside and outside: alpha-synuclein in cortex neurons that produce ACh (learning and memory) and Dopamine (Behavior, motivation)
3. GBA and APOE4

Question 17

Vascular Dementia (VD)
10-30%

Post-stroke and cognitive impairment (VCI)

Risks: HTN, smoking, and high cholesterol

**AD + VCI MOST COMMON

Answer 17

1. Blood vessel blockage –> stroke and brain bleeding
   > determined by location, number and size of infarct
2. First symptom post-stroke
   > Confusion, disorientation, trouble speaking
3. First symptom post multiple strokes:
   > Impaired judgment, attention span, and uncontrollable laughing; motor function difficulties

Question 18

AD (60-80%)

6th leading death cause

Risks: AGE (60), sex (F), genetics and environment

Answer 18

1. Amyloid beta Plaques APP (accumulation causes) neurofibrilary tangles (NFTs)
   > Begins in medial temporal lobe (2 years) with ST memory loss
   > Later with reading, direction, judgment, impulsiveness and visual problems
   > Progressive neurodegeneration: cannot encode and retrieve new information (memory, language, visuospatial)
2. Risk with women
   > Longevity in living
   > heart disease + AD
   > APOE-4 carriers in F
   > Estrogen, mitochondrial toxicity and OxiStress

Question 19

Types of AD

**TOOLS FROM FAD USED TO STUDY SAD

Answer 19

1. Familial:
   > Early onset; APP/PSEN1+2; 40-60; <1% of AD; down syndrome with 3 APP copies
2. Sporadic:
   > Late onset, no known gene; 65+; 99% AD

Question 20

APOE in AD

Answer 20

1. Carries fat and cholesterol through blood stream

2. 3 Variants: APOEv2 is protective

Question 21

More on AD pathological hallmarks

Answer 21

1. APP/Amyloid plaques (AB)
   > Large transmembrane protein for growth/repair
   > Signaling Nexus: info transduction about ECF conditions to ICF signaling events (cell adhesion and binding –> dimerization –> gene regulation + signal trafficking)
   > APP point mutation/copy # duplication increases abnormal B-secretase cleavage –> excess Amyloid accumulation; PSEN1/2 point mutations increase different y-secretase activity
2. NFTs/MAPT: phosphorylated Tau
   > BOTH at low level during normal aging, but diffuses throughout cortex at late stages
   > Hyperphosphorylated Tau proteins destabilize microtubules (info up and down neurons) –> p-tau aggregation

Question 22

Amyloid Beta Hypothesis

**Flaws in production, accumulation or disposal of AB is the primary cause of AD –> NFT formation from altered kinase/phosphatase activities

Answer 22

1. Dominantly inherited form of AD: missense mutation in APP/PSEN1+2 –> increase AB production
2. Non-dominant (sporadic): failure of AB clearance (APOE4 inheritance, faulty Ab degradation) –> gradually rising AB amount in brain

Question 23

Support for BA-Hypothesis

**Still unknown if AB aggregates is the cause or results of disease

Answer 23

1. Patients with APP/PSEN1+2 mutations will get early AD onset
2. 3 copies of APP/T21 has higher plaque burden (higher AD risk)
3. introducing mutated human forms into mice –> plaque and memory problems

Question 24

Tau Hypothesis

Answer 24

1. Amyloid deposition does not correlate with neuronal loss
2. Dementias can be tauopathies
3. Tau pathology in brain and CSF shows higher correlation with memory changes

Question 25

AD Treatment (Stabilization Only)

Answer 25

1. Cholinesterase inhibitors: Aricept > Prevent breakdown of ACh for early stages 2. Memantine: > Regulates glutamate activities in moderate to advanced stages 3. Namzaric combines the two

Question 26

Clinical Trials

Answer 26

1. Drugs stopping Amyloid production, and blocking AB accumulation 2. Drugs that target Tau, heal IS, and decrease blood sugar 3. Dietary supplements, behavioral adjustment and DBS