Neurodegenerative Diseases

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Neurodegenerative Diseases

be able to describe how motor commands are relayed to skeletal muscle and the brain circuitry that controls them

be able to explain the role of the basal ganglia and dopaminergic systems in motor movement

be able to describe happens at the neuromuscular junction

Dopamine: type of catecholamine derived from tyrosine; tyrosine hydroxylase is rate-limiting enzyme; important for mood, motivation, reward, and motor movement

Dopamine Pathways: Mesotcorticolimbic (Mood/Reward); **Nigrostriatal (Motor Control)**

Nigrostriatal Dopamine Pathway: DA neurons live in substantia nigra (mid-brain) -> project to striatum

Basal Ganglia: Inside ventral striatum, consistst of caudate and putamen; DA influences cortical input to basal ganglia

Caudate: Input from motor cortex and sensory association area

Putamen: Gets direct input from variety of sensory cortices and motor cortex

Motor Movement

Structures Involved: SN (filled with DA neurons, send projections to striatum); Striatum with caudate and putamen (receive info from straitum and cortex); Globus Pallidus (internal and external segment -> send info to thalamus)

ENTER PICTURE(S)

Lower Motor Neurons: Live within ventral grey horn of spinal cord (brain stem); innervated by Upper Motor Neurons of cortex, Interneurons, and Stretch Receptors; Actually make contact with skeltal muscle fibers

Neuromuscular Junction

Only generate excitatory post synaptic potentials (EPSPs) in muscle fibers

Releases ACh from LMN (Lower Motor Neurons) terminal --> binds to nicotinic receptors (Increase sodium permability; depolarization causes contractions)

For relaxed muscles, do not stimulate LMN

be able to describe the basics of amyotrophic lateral sclerosis (ALS)

be able to explain the proposed causes, including excess glutamate and excitotoxicity and some of the implicated genes

be able to explain how existing therapies work to help alleviate symptoms or slow degeneration

Description

slow degeneration of LMN and cortical motor neurons, but exclusive to these neurons (not other neurons)

Progressive weakness

wasting of skeletal muscles

Causes

Unknown

Many potential mechanisms ... may have different pathologies that all produce similar symptoms

sporadic ALS: 90% of all patients; radomly develops; environmental influences, mutations/expression?

familial ALS: 10% of all patients; appears to have genetic component

Sporadic ALS

overstimulation of neurons can lead to cell death

increased calcium ions lead to activation of apoptotic pathways

inrease in glutamate leads to increase in NMDA and increase in calcium ions

overexcite and NMDA antagonist --> less neurotoxic effects

many ALS patients have increase of glutamate in CSF

less able to "suck up" glutamate with reuptake inhibitor

BMAA is produced by cyanobacteria that coexist with cycad trees, likely acts on AMPA and NMDA receptors

1960s, Guam: large portion of population suffered from lytico-bodig --> mimics ALS, ALZD, and Parkinson's

Familial ALS

mutations in genetic material that can be inherited --> ALS

SOD1 (superoxide dismutase 1): 20% of all familial cases; SOD1 converts superoxide radicals back to oxygen (O2); radicals can lead to cell death

Alsin: juvenile onset; serves as GTPase regulator

Dynactin: binds to microtubules, allows for vesicular, organelle transport

Functionality in Common Among these Genes

might influence axonal transport: due to the length of both Upper and Lower motor neurons, transport is important

transgenic data: SOD 1 KO = decreased rates of axonal transport

mutant Dynactin = decrease in vesicular trafficking

Treatments

Currently, nothing to help prevent progression... just slow it

Physical Therapy can be helpful esp. with muscle weakness

Riluzole

increases survival time for individual by 2-3 months

most die via slow degeneration of respiratory muscles

MOA: decrease glutamate release, possibly by decreasing glutamate vescicular loading

Butttt.... expensive!!

be able to describe the basics of Parkinson’s disease (PD)

be able to explain what Lewy bodies are and how they are formed

be able to describe classic and novel treatments for Parkinson’s disease and be able to explain HOW they work as a treatment to alleviate symptoms

Description

Motor disturbances, often comorbid with depression

muscular rigidity

tremors at rest

difficulty initiating movments

Cause of these symptoms: degerneration of dopinergic neurons of substantia nigra (SN) (influences inputs/processing in basal ganglia)

Pathology/Causes

Lewy Bodies - globs of misfolded proteins; accumulate in the neuron; accumulation of proteins may be neuroprotective OR cause cells to die

Tend to contain a lot of misfolded alpha-synculein

Inject alpha-synuclein into SN --> causes Lewy bodies to form and # of DA neurons to decrease

Cause of Formation of Lewy Bodies

Genetic Mutations: in familial forms, seems to disrupt ubiquitin-proteasome pathway and/or mitochondria

Oxidative Stress: when a cell makes more free radical than it can eliminate, often manifests as issues with signalling processes

Classical Treatments

goal is to facilitate activity of remaining DA neurons (AGONISTS)

L-DOPA: product of tyrosine hydroxylase, substrate for DA synthesis; helps DA neurons make more DA

Deprenyl: MAO inhibitor (MAOI), stops degredation of DA within presynaptic cell (SE: increases NE and Epi)

Experimental Treatments

Gene Therapy: implant cells directly into body that are genetically modified to effectively increase DA synthesis/release

Stem Cell Grafts: multipotent progenitor cells that will develop into DA neurons; implant w/in striatum

Alpha-synuclein vaccine: promotes generation of anti-alpha-synuclein antibody --> pulls alpha-synuclein out of solution, stop aggregation

be able to describe the basics of Alzheimer’s disease (AD)

be able to describe the pathologies that confirm Alzheimer’s diseasebe able to describe where these would be found within the brain and explain how damage in these areas might produce the hallmark clinical features of AD

be able to explain the role of amyloid precursor protein and presenilin in early-onset AD

be able to describe the risk factors for late-onset and sporadic AD

be able to describe current therapies for Alzheimer’s disease and explain HOW they work

Dementia

loss of memories/inability to form new memories and a decrease in other cognitive functions

steadily progressive

Features of ALZ

Most common form of dementia

Starts with impaired recent memories and attention

Progresses to failure of language skills, difficulties with visual-spatial orientation, abstract thinking, judgement

Neocortex, limbic structures, and brainstem nuclei most affected

Neurofibrillary Tangles: dense protein bundles; aggregation of tau protein (microtubule organizing protein); w/out tau, axons lack appropriate structure.. creates issues

Senile Plaques: extracellular deposits of amyloid beta proteins; within cell, plaques can lead to cell death

Diffuse Loss of Neurons: possibly promoted by excitotoxicity or by apoptosis; acetylcholine neurons are the first to go (abnormal amyloid protein buildup may promote apoptotic pathways in cells

Early-Onset ALZ

Defined by midlife appearance and autosomal-dominant like inheritance pattern

Genetic Factors: amyloid precursor protein (APP) - mutant of gene is cut to form A-B which accumulates into plaques; and presenilin (enzyme) - enhances abnormal cutting of APPP to form pathogenic form of A-B

Genetics: APP - more likely to be cut as a long form A-B

Genetics: gamma-secretase - promote long form A-B cleavage mutation

Late-Onset ALZ

most cases arise sporadically

appear around 60 years

still suggested that A-B aggregation is involved

Experiments

Strittmatter and Salvesen: found ApoE was colocalized with A-B (increased concentration of both in CSF of ALZ)

Pericak-Vance and Roses: families with late onset had a cluster of similar genetic markers on chromosome 19 -- ApoE variant (ApoE4) lives here

ApoE - transports cholesterol through bloodstream; might interfere with long-form A-B clearance ... leads to plaques

Traumatic Brain Injury: closed head injuries increase in number of senile plaques; even larger risk with ApoE4

General Health: decrease in overall general health leads to increase risk of ALZ

Level of Education: positive correlation between education and cognitive performance even with significant plaques

Treatments

Acetylcholinesterase Inhibitors: increase in cognitive .. but doesn't slow degeneration (alleviates symptoms)

Glutamate Antagonists: may slow down neuron cell death by decreasing excitotoxicity

Immunization Against A-B: stimulate body to make antibodies against long-form A-B; effective, but could cause extreme inflammatory reaction in patients