- loss of neurons and/or neuronal fxn
- Cognitive decline during normal aging (perceptual speed, numerical ability, verbal memory)
- knowledge of words still remains
What happens to brains with aging (disease or non-disease)?
- Shrinkage of brain
- loss of neurons and glia cells, but more loss of myelin, dendrites & synapses
What happens to synapses with age?
Synapses decrease, fewer dendritic spines, synapses and branches
How can you help expand life span of synapse while aging?
Caloric restriction: ↓ denervation, ↑ sprouting
What happens to synaptic plasticity in aged animals ?
- 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)
What does GDF-11 do?
- reverses signs of aging in muscle and brain
- greater blood flow
- neural stem cell proliferation
- enhanced olfaction
- skeletal muscle rejuvenation
What are the neurodegenrative disease dealing with protein aggregation?
- Alz plaque and tangles
- Parkinson Lewy Bodies
- Huntington intranuclear inclusion
- Prior amyloid plaques
- Amyotrophic lateral sclerosis
What is the process of misfolding proteins into aggregates?
Native protein -> misfold intermediate -> soluble oligomer -> protofibrils -> fibrils (amyloid)
What protein aggregate are the most toxic in APP?
How do you characterize amyloid ?
Also known as fibrils characterized by β sheets
Why does protein aggregation contribute to Neurodegeneration?
- Loss of fxn
- gain of toxicity
Abnormal,misfolded, infectious proteins that cause correctly folded versions to change conformations and aggregate
How is Alzheimers chareacterzied?
A widespread of neurodengeration that leads to progressive deficits in memory and cognition
What is the typical progression of AD neurogeneration?
- 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
How do you diagnose AD?
- Cognitive impairment, dementia
- amyloid plaques and NFT
Tau in normal neurons vs disease state
- 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
Neurofibriliary tangles (NFT)
- 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)
How is Aβ made?
by cleavage of large transmembrane protein APP (amyloid precursor protein)
What are the most toxic form of oligomers?
- cause the most cell death in a cultured neurons
What are the enzymes that cleave APP?
- α-secretase -> form soluble, okay
What happens when you cleave β + γ at the same time?
Create Aβ -> insoluble -> oligomers
What is the problem when too much APP is cleaved?
- Normally is harmless and fxnl
- problem when there is a mutation or inbalance that result in too much Aβ42 formation
What are the 2 forms of AD
- Early onset
- genetic base, 50% risk value (autosomal dominate)
- mutation in APP, PSEN1/2
- Late onset
- most common
- genetic risk factor: ApoE4
How do mutations in familial AD (APP, PSEN1/2) lead to early-onset of AD?
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
What are th 3 common alleles of ApoE?
defined by changes in 2 amino acids that change the affect of how the protein fxns
What ApoE associated with sporadic AD
Helps clear out Aβ from brain
What is the Amyloid Cascade Hypothesis?
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
What are the machineries to diagnose AD?
- MRI: look fo neurodengeneration
- PET scan: look for amyloid (Pib binds to β-sheets structure in insoluble Aβ protofibrils and fibrils)
What is the treatment for AD?
- Use to treat dementia in AD
- 1. Acetylcholinesterase inhibitor: boost transmission of dying Achergic neurons
- 2. NMDAR blocker: block excitotoxicity
What are new AD treatments being developed ?
- Inhibit formation of AB42- secretase inhibitors
- immunotherapy to clear out Aβ
What is the underlying problem of Parkinson's Disease?
Loss of DA neurons in the SN
What are the major motor symptoms?
- Hypokinetic disorder
- difficulty initiating mvnt (akinesia)
- slower mvnt (bradykinesia)
What machinery is used to is PD in brain?
PET scan, using fluorodopa labels DAergic synapses in striatum
How is the basal ganglia altered in PD?
- Activate the indirect pathway of BG
- increase inhibition to thalamus -> less stimulation of motor areas in cortex -> less mvnt
Why is the neuron loss primary in substantia nigra?
Neurons in the SN have intrinsic rhythmic electrical activity (pacemakers) which require a great deal of ATP -> most vulnerable to degeneration
Why are the neurons in the SN particular vulnerable to degeratation?
SN pacemaker -> ↑ ATP -> ↑cellular respiration -> ↑ROS -> creates damage -> kill cells
What is MPTP used for?
- 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
What are environmental factors for PD?
(ROS)Oxidative stress -> mitotic damage -> excitotoxocity, inflammation -> cell death
What are the genetic factors assocaitated with PD?
- A-synuclein, PINK1, Parkin
- cause protein aggregating -> Lewy bodies ->cell death
Can be both familial or sponateous (most not inherited)
What is the role of PINK1 and Parkin?
- 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
What are the stages of severity of PD?
- 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
What is the prion-nature of α-synuclein?
- Small a-synuclein fibrils can move form neuro to neuron
- once inside cell, pick up normal a-synuclein -> make Lewy bodies
What are the therapeutic strategies focus to decrease a-syn aggregates ?
- 1. Autophagy: increase clearance
- 2. Cleavage: reduce aggregation
- 3. Oligomers: reduce aggregation
- 4. Immunotherapy: reduce aggregation
What are the types of treatments for PD?
- 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
What causes Huntington Disease?
- Repeated CAG in Huntington (htt) gene
- has age onset of 35-45yrs
What are the physical symptoms of HD?
- 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
Where does Neurodegeneration occur for HD?
Neuron loss starts in striatum of basal ganglia -> less output to indirect pathway -> less inhibition of thalamus -> more excitation to cortex -> hyperkinetic disorder
What area the Huntingtin gene and protein ?
- 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
What experiment showed CAG repeats are SUFFICIENT for HD neuronal pathology?
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
What experiment showed CAG repeats are SUFFICIENT for HD motor phenotype?
Mice showed characteristic clasping compared to control
What experiment showed CAG repeats are NECESSARY for HD neuronal pathology?
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
What is the normal function of Huntington
- 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
If mHTT is targeted for distruction by proteasome, why keep occurring ?
- 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
What is the importance of Htt and BDNF signaling from cortex to striatum?
- 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
What are current treatment for HD?
- 1. Tetrabenazine: treat chorea; VMAT2 inhibitor
- 2. 2nd generation atypical neuroleptic : treat psychiatric symptoms (DA and 5HT receptor antagonist)
- 3. SSRIs: treat depression
What are future treatment plans for HD?
- 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
What are the symptoms of MS?
- Depends on where demyelination and neurodengeration occurs
- numbness, tingles, dizziness, difficult walking, vision problems, muscle spasms, fatigue, pain
What are the 4 clinical patterns of MS progression?
- Relapsing remitting MS (RRMS), inflammation
- Secondary Progressive MS (SPMS), Neurodegeneration
- Primary Progressive MS (PPMS)
- Progressive Relapsing MS (PRMS)
How do you diagnose MS?
- 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
What is the autoimmune response to MS?
- 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
How does myelin degeneration lead to axon degeneration ?
- 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
How can you get remyelination?
- Oligodendrocytes precursor cells are recruited to damage site where they differentiate and reward the axon n
- abilty to remyelinate decreases with age
What stage of MS likely corresponds to the remyelination?
- in later stages of MS -> major axon loss
- 70% of axons lost -> paralysis
What are the genetic and environmental factors associated with MS?
- 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
How do you treat for MS?
- Have disease modifying drugs decreasing immune response and inflammation
- most target the RRMS stage -> reduce proliferation of T-cells
What are alternating treatments for MS?
- 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
Catastrophic brain injury
Intracranial bleeding; blood vessel break and bleeding causes increase of pressure
Mild traumatic brain injury (TBI)
Concussion can have both immediate and long term effect
What is the immediate response to mild traumatic brain injuries?
- Unconcousiousness if severe TBI
- dizziness, nausea, memory problem
What is the long term effects response to mild traumatic brain injuries?
- 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)
Diffuse axonal injury (DAI)
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
Tau and NFT in TBI
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
What is the pathological criteria for diagnosis of chronic traumatic encephalopathy
Perivascular foci of p-tau immunoreactivity ATs and NFTs