MCB 165

• loss of neurons and/or neuronal fxn
• Cognitive decline during normal aging (perceptual speed, numerical ability, verbal memory)
• knowledge of words still remains

• Shrinkage of brain
• loss of neurons and glia cells, but more loss of myelin, dendrites & synapses

Synapses decrease, fewer dendritic spines, synapses and branches

Caloric restriction: ↓ denervation, ↑ sprouting

• Synaptic plasticity is impaired
• used pair pulsed facilitation and depression to test LTP and LTD -> saw smaller response change of EPSP 
• however old-aged synapse still undergo some potentiatation

• Connect blood vessels of young and old mice
• help improve the impairment of neurogenesis of old mice with young blood due to growth factor (GDF11)

• reverses signs of aging in muscle and brain 
• greater blood flow
• neural stem cell proliferation 
• enhanced olfaction
• skeletal muscle rejuvenation

• Alz plaque and tangles
• Parkinson Lewy Bodies
• Huntington intranuclear inclusion 
• Prior amyloid plaques
• Amyotrophic lateral sclerosis

Native protein -> misfold intermediate -> soluble oligomer -> protofibrils -> fibrils (amyloid)

Soluble oligomers

Also known as fibrils characterized by β sheets

• Loss of fxn
• inflammation 
• gain of toxicity

Abnormal,misfolded, infectious proteins that cause correctly folded versions to change conformations and aggregate

A widespread of neurodengeration that leads to progressive deficits in memory and cognition

• Preclinical: hippocampal region affected first, rent episodic memory loss 
• mild-moderate: more cortical areas affected, persistent mem loss (STM and start LTM), mood changes 
• severe: most cortical areas affected, confused past and present, lose ability to communicate, motor impairment, hallucination

• Cognitive impairment, dementia
• amyloid plaques and NFT

• normal: tau protein is phosphorlated a few times and binds to microtubles to help stablize them 
• disease: tau is hyperphosphorylated -> releases MT -> depolymerizes and shrink MTs

• Is hyperphosphorylated tau
• is bad bc no more axonal transport and forms insoluble aggregates inside neurons

• Are aggregates of insoluble proteins that are extracellular 
• made of beta amyloid (Aβ)

by cleavage of large transmembrane protein APP (amyloid precursor protein)

• AB42 
• cause the most cell death in a cultured neurons

• β-secretase
• α-secretase -> form soluble, okay 
• γ-secretase

Create Aβ -> insoluble -> oligomers

• Normally is harmless and fxnl
• problem when there is a mutation or inbalance that result in too much Aβ42 formation

• Familial AD
• Sporadic AD

• Early onset
• genetic base, 50% risk value (autosomal dominate) 
• mutation in APP, PSEN1/2

• Late onset
• most common
• genetic risk factor: ApoE4

APP has diff conformation that makes it more likely go oligomer state -> increase Aβ42

• Found in lipoproteins 
• plays a role in cholesterol and lipid homestasis in the CNS

• E2
• E3
• E4

defined by changes in 2 amino acids that change the affect of how the protein fxns

ApoE4

Helps clear out Aβ from brain

AD starts with the build up of Aβ oligomers BUT a substantial # of older ppl have amyloid plaques w/o cognitive problems 

therefore, AD is a complex disease caused by many diff factors

• MRI: look fo neurodengeneration
• PET scan: look for amyloid (Pib binds to β-sheets structure in insoluble Aβ protofibrils and fibrils)

• Use to treat dementia in AD
• 1. Acetylcholinesterase inhibitor: boost transmission of dying Achergic neurons 
• 2. NMDAR blocker: block excitotoxicity

• Inhibit formation of AB42- secretase inhibitors
• immunotherapy to clear out Aβ

Loss of DA neurons in the SN

• Hypokinetic disorder
• difficulty initiating mvnt (akinesia)
• slower mvnt (bradykinesia)

PET scan, using fluorodopa labels DAergic synapses in striatum

• Activate the indirect pathway of BG
• increase inhibition to thalamus -> less stimulation of motor areas in cortex -> less mvnt

Neurons in the SN have intrinsic rhythmic electrical activity (pacemakers) which require a great deal of ATP -> most vulnerable to degeneration

SN pacemaker -> ↑ ATP -> ↑cellular respiration  -> ↑ROS -> creates damage -> kill cells

• Induces Parkinson-like symptoms
• used to make PD models 
• MPTP -> MPP+ which goes into DA neurons-> inhibit complex 1 in electron transport chain -> ATP depleted, build ROS

(ROS)Oxidative stress -> mitotic damage -> excitotoxocity, inflammation -> cell death

• A-synuclein, PINK1, Parkin 
• cause protein aggregating -> Lewy bodies ->cell death

Can be both familial or sponateous (most not inherited)

• Help destroy damaged mitochondria 
• 1. PINK1 in mitotic membrane-- healthy mito cleaves PINK1 OR PINK1 accumulates on damaged mito 
• 2. PINK1 recruits Parkin
• 3. Parkin ubiquitinates substrates in mito membrane 
• 4. Mito marked for destruction by autophagosome or lysosomes

• Causes dominant forms of familial PD
• By a single base pair change in SCNA that change one AA

interacts with SNARE complex to cluster sympatic vesicles at presynaptic membrane

aggregate into Lewy bodies inside neurons 

• Intercellular inclusions 
• fibril

• Spread of Lewy bodies correlate with severity 
• stage 1&2: autonomic and olfactory disturbance 
• stage 3&4: sleep and motor disturbance
• stage 5&6: emotional and cognitive disturbance

• Small a-synuclein fibrils can move form neuro to neuron 
• once inside cell, pick up normal a-synuclein -> make Lewy bodies

• 1. Autophagy: increase clearance
• 2. Cleavage: reduce aggregation
• 3. Oligomers: reduce aggregation
• 4. Immunotherapy: reduce aggregation

• Levodopa & Carbidopa : DA replacement, improve mvnt only for 5-10yrs
• Deep Brain Stimulation: stimulation to GPi and STN decrease inhibition to cortex, used after L-DOPA stops working 
• Cell Base Therapies: use other DA neurons in body and transplanted it patients OR use stem cells to convert them to DA

• Repeated CAG in Huntington (htt) gene
• has age onset of 35-45yrs

• Hyperkinetic 
• Difficultly maintaining grip 
• chorea: involuntary body mnvt
• fine motor mvnt skills impaired, eye mvnt abnormablities, slurred speech
• depression, anger, psychosis 
• difficulty concentrating and multitasking 
• fatal in 10-20yrs

Neuron loss starts in striatum of basal ganglia -> less output to indirect pathway -> less inhibition of thalamus -> more excitation to cortex -> hyperkinetic disorder

• Genetic linkage: htt gene on chromo 4
• protein: has more protease and cut into smaller piece -> form oligomers and aggregates 
• Poly-Q: polyglutamine repeats, if repeat >40 -> mut form -> cause HD

• More CAG repeats - earlier onset
• CAG can expand durng DNA replication -> makes HD more severe through generations

CKO: CAMKIIa X LacZ+enhancer+CAG -> turn on htt gene

• saw staining for poly-Q htt show aggregates in nuclei and extracellulary
• saw smaller brain, loss of striatal neurons

Mice showed characteristic clasping compared to control

CKO: CAMKIIa +DOX X LacZ+enhancer+CAG -> turn off htt gene

• Mice expressed poly-Q Htt for 1st 18 weeks
• DOX turns off expression of polyHtt -> reversible effect and reverse clasping behavior

• Not the toxic component of HA
• aggerates are more likely protective, a way to sequester more toxic oligomers 
• but bind to other normal proteins -> more CAG -> more misfolding -> more oligomers

• Interact w/ motor protein, axonal transport of vescicles 
• help regulate tx factors: htt binds to repressor (REST) in cytoplasm and hold it so it won't go into the nucleus->> BDNF able to signal

• Too much mHTT, proteasome becomes impaired and can't fxn at optimal level
• cant destroy all cells -> ↑ Oligomers -> ↑ aggregates -> affect vesicle transport and to regulation

Important for neuron survival and plasticity

• Striatum does not make own BDNF and rely on cortical signaling 
• if stiratal neurons don't receive the pro-survival signal, will die off 

see 50% reduction of BDNF if brains of HD patients

• 1. Tetrabenazine: treat chorea; VMAT2 inhibitor 
• 2. 2nd generation atypical neuroleptic : treat psychiatric symptoms (DA and 5HT receptor antagonist)
• 3. SSRIs: treat depression

• 1. Antisense oligonucleotides (ASO): inhibit RNA of mHTT translation
• 2. CRISPR/Cas9: gene editing

• An autoimmune disease caused by chronic inflammation in the CNS
• Demylination and neural degeneration 
• characterized by multiple sclerotic plaques (lesions) visualized in MRI
• Onset: 20-40 yr old

• Depends on where demyelination and neurodengeration occurs 
• numbness, tingles, dizziness, difficult walking, vision problems, muscle spasms, fatigue, pain

• Relapsing remitting MS (RRMS), inflammation
• Secondary Progressive MS (SPMS), Neurodegeneration 
• Primary Progressive MS (PPMS)
• Progressive Relapsing MS (PRMS)

RRMS

SPMS

PPMS

PRMS

• 1. Have multiple lesion in white matter in MRI ->lesion contain demyelinated neurons and immune cell 
• 2. Only diagnosed after 2 incidences of neurological symptoms space by a few months

• 1. Immune cells come reactive to myelin 
• 2. Immune cells cross BBB into CNS
• 3. Activate microglia to release cytokines
• 4. Direct T cells to myelin oligodendrocytes and neuron -> kill myelin

• Microglia consome degrading axon
• 1. Axons tries to compensate by increasing voltage-gated channels along the axon (as it loses myelin)
• 2. Too much Na+ inside -> Na/K pump works harder
• 3. More Ca+ into cell -> activate proteases (enzyme that destroys protein)

myelin (oligodendrocytes) provide metabolic/tropic support to axon, and w/o it axons will die

• Oligodendrocytes precursor cells are recruited to damage site where they differentiate and reward the axon n
• abilty to remyelinate decreases with age

• RRMS
• in later stages of MS -> major axon loss 
• 70% of axons lost -> paralysis

• HLA genes: high assocaition
• low vitamin D: metabolite of vit D suppress immune system 
• Epstein-Barr and Herpes virus: infection may cause production of antibodies that can cross react w/ myelin proteins

• Have disease modifying drugs decreasing immune response and inflammation
• most target the RRMS stage -> reduce proliferation of T-cells

• MS symptoms increase with heat
• use cooling vest
• anything that can inhibit voltage gated K+ channels, axon can't repolarize as well 
• medical marijuana, help relieve pain/ lessen severe symptoms

Intracranial bleeding; blood vessel break and bleeding causes increase of pressure

Concussion can have both immediate and long term effect

• Unconcousiousness if severe TBI
• dizziness, nausea, memory problem

• CTE
• NFTs in brain, Neurodegeneration 
• impaired balance, coordination, Hypokinetic 
• attn and memory disturbances, depression, aggression

• Bruise, look vessel break
• can occur at site of injury (coup) or opposite side (contre-coup)

Mechanical force can shear the axons -> form bulb attempts to retract (interrupt axonal tranport and axonal bulb formation and diffusion of misfolded proteins)

use Diffusion tensor imaging MRI to look at tracts/ white matter

Primary injuries of neurons and glia lead to hyperphosphorylated tau -> forms NFT in nuerons and astrocytes 

Inbalance between kinases and phosphatase w/ hyperphosphorylation of tau  -> tau aggeration into NFT and neuropil threads

Perivascular foci of p-tau immunoreactivity ATs and NFTs