MM-Essential neuroscience Part B Flashcards
Astrocytes
-starshaped
-Highly Branched
- Non-Overlapping domains
Composition of Astrocyte network
Glial Syncytium-Gap Junctions- movement of water and ions (small molecules) between Astrocytes
The role of the Tripartite synapse
Astrocyte membrane receptors allow monitoring and support of the pre and Post synaptic junction.
Glutamate transporters are expressed on the astrocyte membrane:
-removal of excessive neurotransmitter Glutamate.
(maintain efficient transmission and prevent desensitisation of post-synapse)
-recycling of glutamate to glutamine, which is then secreted from the astrocyte for uptake and reuse
Astrocytes act as a network for Potassium Spatial Buffering
Astrocyte membrane is hyper-polarised but not excitable (-80mV)
Potassium channels are abundant on the astrocyte membrane and allow inward flow of K+
K+ taken up from areas of high concentration can be shared across the network along chemical
gradients.
Calcium signalling in the astrocyte network
Astrocyte not electrically excitable-can use Ca2+ to synchronise activity.
stimulation with glutamate- Internal Ca2+ oscillation.
release of Ca2+ stores linked to release of Gliotransmitters.
Gliotransmitters
Glutamate
ATP
D-serine
TNF alpha
Neurovascular coupling
Higher neuron activity requires increased blood flow.
Activation of metabotropic (long lasting) glutamate receptors (mGluR) -intracellular Ca2+ stores released:
1-Production of vasodilation inducing cyclooxygenase (COX)
2-Opening of ‘big potassium channels’ (BK), increasing
extracellular K+ concentration -vasodilation
Blood-Brain Barrier maintenance
-Trophic support:
Glucose
Hormones
Lipids
Amino acid
-removal of waste products
main form of energy production in the brain.
Oxidative phosphorylation
-Metabolic flexibility allows neurons to switch to glycolysis under
anaerobic conditions
(however neurons do hold a large store of glucose/glycogen)
Pyruvate-Lactate Shuffle
1.Astrocytes transport glucose
from the vasculature (bv).
2.Astrocytes can store glucose by
converting to glycogen.
3.Glucose is converted to pyruvate for astrocyte metabolism.
- Astrocytes convert pyruvate to lactate by Lactate dehydrogenase.
5.Lactate is release for uptake by neurons via monocarboxylate transporters.
6.Lactate is converted to pyruvate by lactate dehydrogenase for neuron oxphos metabolism.
summary of Astrocytes in brain health and function
- Regulating blood flow and supply of oxygen (Neurovascular unit)
- Clear excessive neurotransmitter from synaptic cleft
- Regulate ion homeostasis
- Signal to neurons and glia by release of ‘gliotransmitters’
- Provide metabolic support to neurons
role of Microglia
- is a Macrophage
- ## surveillance and monitoring of brain health.
Neuroinflammation
a mixed cellular response to brain
infection or damage involving innate and adaptive responses of
resident brain cells and circulating immune cells
The 2 stages of Microglia activity
- Homeostatic -Rumified Shape
- Reactive
In its Active form Microglia…
secrete inflammatory Cytokines - activating other glial cell activity
microglial Phagocytosis
- Phagocytose Invading pathogens
-refine neural circuits by pruning ‘weak’ synapses
Pruning of weak synapses
-Weak synapses are labelled by C1q and C3, compliment factors.
-microglia detect compliment factors on the synapse using C3 receptors
-engulf material
Neurodegenerative Disease
-progressive neurological diseases where neurons loose function and die
two sub-classes:
-Movement Disorders
-Dementia
Dementia
-Family of diseases associated impairment of cognitive function
-age associated loss of memory,
reasoning, judgement and executive function.
Alzheimer’s disease
Vascular dementia
Frontotemporal dementia Sclerosis
Dementia with Lewy Bodies
Alzheimer’s disease
Cognitive Symptoms: Primary symptoms of AD are a loss of memory and cognitive function
Psychiatric symptoms: Delusions, hallucinations, depressed mood, and agitation (including violent outbursts)
Physiological Problems: disrupted sleep, incontinence, and difficulty swallowing are seen.communication skills are diminished, social withdrawal, loss of language
Vascular dementia
Small vessel disease associated with ‘mini-strokes’, variable cognitive dysfunction
Frontotemporal dementia
Behaviour, mood, personality.
Related to Amyotrophic Lateral Sclerosis
Dementia with Lewy Bodies
Cognition, visual perception, sleep
disruption. Related to Parkinson’s Disease
therapeutics for Alzheimer’s disease
Memantine:
-NMDA glutamate receptor antagonist Preferentially block overactive NMDA glutamate receptors
Rivastigmine, Galantamine, Donepezil:
-Acetyl-cholinesterase inhibitors Block breakdown of acetyl-choline in the synaptic cleft
Alzheimer’s Disease leads to pronounced degeneration of which parts of the ageing brain
- Cerebral Cortex: higher level processing, memory, reasoning,
language, thought, emotion - Hippocampus: encoding short term memory, consolidating
long term memory - Entorhinal Cortex: network point allowing information to
enter and leave the hippocampus
what two abnormal deposits are found in an Alzheimer’s brain ?
- Neurofibrillary Tangles
- Amyloid Plaques / senile Plaques
Amyloid Plaques / senile Plaques
-Large extracellular protein
accumulations
primarily composed of amyloid beta (Aβ42)– a 42 amino acid fragment of the Amyloid Precursor Protein (APP)
Neurofibrillary Tangles
-fibrous intracellular inclusions in neuron cytoplasm.
-Composed of hyperphosphorylated tau protein (noromally associated with cytoskeleton microtubules)
Pyramidal neurons are particularly
susceptible to NFT formation
Spread of Amyloid Plaque and Neurofibrillary Tangle Pathology during AD progression
Neurofibrillary Tangles:
Detected in entorhinal cortex during early stages of AD - Spread to Cortex and Hippocampus during disease
progression
Amyloid Plaques:
First occur in cerebral cortex -
Spread to hippocampus and distribute widely throughout AD progression
Role of non-nueronal cells in AD Pathology
Microglia:
Become reactive- direct contact with amyloid plaques
reactivate pruning, removing adult
synapses
Astrocytes:
-Reactive astrocytes release pro-inflammatory cytokines
-Downregulate glymphatic clearance activity
Vasculature:
-Breakdown of blood brain barrier
-allowing normally restricted
molecules systemic circulation to enter the brain
i.e. inflammatory factors, peripheral immune cells
Mutations in APP and gamma secretase enzymes are associated with early onset Alzheimer’s disease
Motor Neuron Diseases
Family of diseases associated with death of motor neurons
- loss of motor neurons from
cortex, brainstem and spinal cord
Primary Motor Cortex
Amyotrophic lateral sclerosis (ALS)
- Muscle stiffness, fasciculations, weakness
loss of neuromuscular junction connections
SOD1(Superoxide Dismutase 1 ) -over expression results in loss of motor function.
TDP43- splcing of s
(No Muscle Nourishment Lateral Scarring)
Gene Therapy for ALS
Tofersen:
-Antisense oligonucleotide (ASO) drug -blocks production of SOD1, reducing production of aggregating protein
-uses synthetic single stranded RNA to disrupt gene expression
