Lecture 2: Pathophysiological mechanisms
in neurodegenerative disorders
General concept of neurodegeneration
- Eyes and brain are closely connected → they develop together in embryogenic stage
- Retina (netvlies): made out of neurons (such as the brain)
,- Neurodegeneration:
o Combination of two words “neuro”, referring to nerve cells and
“degeneration”, referring to progressive cell damage
- Neurodegenerative diseases:
o Represent a large group of neurological disorders with heterogenous clinical
and pathological expressions affecting specific subsets of neurons
o A few hundred neurodegenerative diseases exist
o Most attention has been given to AD (Alzheimer’s Disease), PD (Parkinson’s
Disease), HD (Huntington Disease), and ALS (Amyotrophic Lateral Sclerosis)
- Cellular cascade:
o Neurodegeneration is initiated by metabolic disruption events in the neurons,
such as protein overexpression or misfolding. These events activate microglial
cells and the Blood Brain Barrier (BBB), sending signals (cytokines) which
induce inflammation in the brain. Inflammation leads to neuronal damage
and finally neurodegeneration.
- What causes neurodegeneration? mostly unknown
o With few exceptions, the causes of neurodegenerative diseases are
essentially unknown, and even when they have been identified, the
mechanisms by which they initiate the disease remain unknown.
▪ While the etiology of HD was identified >20 yrs ago, we still do not
know how mutant huntingtin provokes the disease
▪ Even if you know what the cause is (such is protein misfolding), then
they still don’t know what causes this protein to cause
neurodegeneration
o Some neurodegenerative disorders have a clear familial occurrence,
suggesting a genetic basis. Among these affected families, the disease runs as
an autosomal dominant trait, as in HD. Others are essentially sporadic but
show a small contingent of patients in whom the illness is inherited
,Pathophysiology of AD
= Alzheimer’s Disease
= An irreversible, progressive brain disorder that accounts for 50-
75% of all cases of dementia (10-20% is vascular dementia)
- AD is NOT the same as dementia
- 3 hallmarks
o Brain atrophy
▪ Shrinkage of the brain
▪ 2 typical places: cerebral cortex +
hippocampus
▪ Enlarged ventricles
o Extracellular aggregates of amyloid β (Aβ) plaques
▪ Due to defect in APP (Amyloid Precursor Protein) processing
• Normally: APP gets cleaved at a-secretase → sAPP (soluble)
• If APP gets cleaved at β-or g-secretase → Aβ (amyloid beta) →
very hydrophobic and sticky → senile plaque formation
, o Intracellular neurofibrillary tangles made of hyperphosphorylated
tau-protein (Tau tangles)
▪ Tau: normally stabilizes the microtubule in axons
▪ But if it is hyperphosphorylated → get’s sticky and gets of the
microtubule → loses its function of stabilization → gets tangled,
clumped together
- Clinical disease process
- It normally starts with amyloid beta plaques: no problems, no symptoms, 10-20 years
before diagnosis → TAU → after a while clinical disease stage: memory problems
o When you get diagnosis: it is already too late, you can’t get rid of the plaques
o So, if you have no symptoms, you can’t prevent it
- 47 million people worldwide suffer from dementia
o Every 3 seconds new cases are diagnosed
o All people with Alzheimer suffer from dementia, but not all dementia cases
are due to Alzheimer pathology
o No treatment for AD
o Not all subjects with amyloid plaques suffer from dementia
in neurodegenerative disorders
General concept of neurodegeneration
- Eyes and brain are closely connected → they develop together in embryogenic stage
- Retina (netvlies): made out of neurons (such as the brain)
,- Neurodegeneration:
o Combination of two words “neuro”, referring to nerve cells and
“degeneration”, referring to progressive cell damage
- Neurodegenerative diseases:
o Represent a large group of neurological disorders with heterogenous clinical
and pathological expressions affecting specific subsets of neurons
o A few hundred neurodegenerative diseases exist
o Most attention has been given to AD (Alzheimer’s Disease), PD (Parkinson’s
Disease), HD (Huntington Disease), and ALS (Amyotrophic Lateral Sclerosis)
- Cellular cascade:
o Neurodegeneration is initiated by metabolic disruption events in the neurons,
such as protein overexpression or misfolding. These events activate microglial
cells and the Blood Brain Barrier (BBB), sending signals (cytokines) which
induce inflammation in the brain. Inflammation leads to neuronal damage
and finally neurodegeneration.
- What causes neurodegeneration? mostly unknown
o With few exceptions, the causes of neurodegenerative diseases are
essentially unknown, and even when they have been identified, the
mechanisms by which they initiate the disease remain unknown.
▪ While the etiology of HD was identified >20 yrs ago, we still do not
know how mutant huntingtin provokes the disease
▪ Even if you know what the cause is (such is protein misfolding), then
they still don’t know what causes this protein to cause
neurodegeneration
o Some neurodegenerative disorders have a clear familial occurrence,
suggesting a genetic basis. Among these affected families, the disease runs as
an autosomal dominant trait, as in HD. Others are essentially sporadic but
show a small contingent of patients in whom the illness is inherited
,Pathophysiology of AD
= Alzheimer’s Disease
= An irreversible, progressive brain disorder that accounts for 50-
75% of all cases of dementia (10-20% is vascular dementia)
- AD is NOT the same as dementia
- 3 hallmarks
o Brain atrophy
▪ Shrinkage of the brain
▪ 2 typical places: cerebral cortex +
hippocampus
▪ Enlarged ventricles
o Extracellular aggregates of amyloid β (Aβ) plaques
▪ Due to defect in APP (Amyloid Precursor Protein) processing
• Normally: APP gets cleaved at a-secretase → sAPP (soluble)
• If APP gets cleaved at β-or g-secretase → Aβ (amyloid beta) →
very hydrophobic and sticky → senile plaque formation
, o Intracellular neurofibrillary tangles made of hyperphosphorylated
tau-protein (Tau tangles)
▪ Tau: normally stabilizes the microtubule in axons
▪ But if it is hyperphosphorylated → get’s sticky and gets of the
microtubule → loses its function of stabilization → gets tangled,
clumped together
- Clinical disease process
- It normally starts with amyloid beta plaques: no problems, no symptoms, 10-20 years
before diagnosis → TAU → after a while clinical disease stage: memory problems
o When you get diagnosis: it is already too late, you can’t get rid of the plaques
o So, if you have no symptoms, you can’t prevent it
- 47 million people worldwide suffer from dementia
o Every 3 seconds new cases are diagnosed
o All people with Alzheimer suffer from dementia, but not all dementia cases
are due to Alzheimer pathology
o No treatment for AD
o Not all subjects with amyloid plaques suffer from dementia
