Alzheimer - L12 Flashcards
What are the pathological hallmarks of Alzheimer’s disease?
- Amyloid beta plaques
- Neurofibrillary tangles
Describe how amyloid-beta plaques arise.
Amyloid Precursor Protein (APP) is normally cut by α-secretase, where non-amyloidogenic amyloid protein is produced as a consequence. But if APP is cleaved by β- en γ-secretase, amyloidogenic amyloid is produced that is either 40 or 42 amino acids long.
Which immune cells are responsible for the removal of amyloid-beta plaques?
Microglia and astrocytes
How are tau-tangles formed?
Normally, tau is important for the stabilization of microtubules. During the transport of products by kinesin over microtubuli, tau is dephosphorylated and phosphorylated by phosphatases and kinases, respectively.
Tau-tangles arise when tau is hyperphosphorylated by kinases such as GSK-3β. This causes them to detach from microtubuli. Tau is now able to aggregate and can no longer stabilize microtubuli, causing unstable microtubuli. Due to their small size, they are able to accumulate in neurons.
The dynamic equilibrium between phosphorylation and dephosphorylation of tau proteins is disrupted in Alzheimer’s. How?
- There is an increase Tau kinases
- There is a decrease in Tau phosphatates
What is the amyloid cascade hypothesis?
It states that amyloid-beta (AB) is the most important player that causes cognitive dysfunction.
Here, accumulation of AB leads to oligomerization of AB and formation of diffuse plaques. AB oligomers affect synapses, which causes microglia and astrocyte acitvation that damages synapses and neurites even more. This causes alteration in neuronal ionic homeostasis, which disrupts the function of tau, hyperphosphorylating tau and creating tau-tangles. These tau-tangles cause neuronal/neuritic dysfunction and cell death. This ultimately leads to dementia.
Name consequences of the accumulation of misfolded proteins and neurodegeneration.
- Oxidative stress
- Protein sequestration
- Disruption of axonal transport
- Synaptic dysfunction
- Inhibition of UPS
- Mitochondrial dysfunction
During the progression of neurodegenerative diseases such as Alzheimers, there is a steady spread of misfoled proteins. Describe how misfolded proteins can spread through the brain.
Spreading of misfolded proteins via synapses:
* Use of exosomes
* Use of endosomes
* Via receptors
* Via nanotube
Many other neurological disorders are
characterized by a build-up of protein
aggregates in the brain. Why is the brain
especially vulnerable to these protein
aggregates?
- Post-mitotic state of neurons
- High metabolic rate
- Complex cellular structure
- Blood-brain barrier
- Limited cellular repair mechanisms
- Long lifespan of neurons
Name characteristics of microglia.
- Major immune cells of the brain
- Important for brain homeostasis
- Shape neural circuits
- Phagocytosis, APCs, activating T cells
- Function and morphology are connected
What are ramified and unramified microglia?
- Ramified: a resting form of microglia composed of long branching processes and a small cellular body. By having multiple long branches, they are able to chemically sense their surroundings.
- Unramified: often amoeboid shaped and seen as an activated form where they are able to move around the nervous system and phagocytose pathogens etc.
What kind of evidence is there regarding the role of inflammation in alzheimer’s?
- GWAS: genes that impact microglial activation
- Mutations in acute phase proteins and cytokines
- Protective variant: PLCG2 reduces risk for neurodegeneration in general (microglial expression)
Describe characteristics of the inflammatory response in alzheimer’s disease.
- Presence of complement activated products, acute phase proteins, cytokines, activated microglia
- Absence of immunoglobulins, T- and B-lymphocytes, upregulation of adherins and selectins on endothelial cells.
How could Alzheimer’s disease be treated?
Through the use of immunotherapy (active or passive immunization against amyloid beta plaques or tau tangles.
What other pathology is associated with increasing tau?
Traumatic brain injury
