Neuropathology 2 Flashcards
What is a neurodegenerative disease? Give some examples.
A neurodegenerative disease is a heterogeneous group of illnesses with the common feature of progressive neuronal cell loss, but distinct clinical phenotypes and genetic aetiologies:
- Alzheimer disease (AD)
- Parkinson disease (PD)
- Huntington disease (HD)
- Friedreich ataxia (FRDA)
Outline Alzheimer disease (AD).
AD is the most common neurodegenerative disease and is the most common cause of dementia. It progresses in defecting memory, cognition, attention and motivation. There are about 1 million cases of AD in the UK and there is an increasing incidence (1/4 people).
Pathologically the cortex of the brain shrinks and the two classical lesions in the CNS are β-amyloid plaques (extracellular matrix) and neurofibrillary tangles (intracellular tau).
What is the function of β-amyloid peptide (Aβ)?
Aβ peptide is generated by proteolytic cleavage of the amyloid precursor protein (APP) with β- and γ-secretase.
Aβ is normally produced in the brain where it appears to be an antioxidant involved in metal ion homeostasis.
Over-expression of APP (increased Aβ) occurs in Down syndrome, following brain ischaemia or head injury, and by mutations in APP or γ-secretase genes.
Outline familial AD.
5% of all AD cases are familial, and are autosomally dominant with early onset (<60). Mutations have been identified in:
- Amyloid precursor protein (APP) gene (1% missense)
- Presinilin-1 (PS1) gene (γ-secretase)
- Presinilin-2 (PS2) gene (γ-secretase)
Sporadic AD and late-onset familial AD are associated with _____________ of the ______________ E (apoE) gene.
Inheritance of APOE __ alleles and _____ gene variants are associated with increased risk of AD.
APOE __ allele may confer some protection from the development of AD.
Sporadic AD and late-onset familial AD are associated with polymorphism of the apolipoprotein E (apoE) gene.
Inheritance of APOE ε4 alleles and TREM2 gene variants are associated with increased risk of AD.
APOE ε2 allele may confer some protection from the development of AD.
What is used to treat Alzheimer disease (AD)?
Acetylcholinesterase inhibitors, which potentiate (incerase power of) the effects of ACh release in the cortex from cholinergic neurons, and it can produce a modest improvement in some patients.
Anti-inflammatory drugs can arrest cognitive decline.
Novel strategies are being investigated include inhibitors of Aβ production, e.g. g-secretase inhibitors.
Describe the pathology of Alzheimer disease (AD).
AD brains show cortical atrophy and hydrocephalus ex vacuo (enlarged CSF spaces). Gyri narrow, sulci widen and cortical atrophy is especially apparent in the parahippocampal regions. However, as the disease progresses, atrophy of temporal, frontal and parietal cortex becomes more severe.
Senile plaques and neurofibrillary tangles (NFTs) dominate AD histology. The most conspicuous histologic lesions, are extracellular spherical deposits of β-amyloid several hundred microns in diameter. In end-stage disease, senile plaques occupy large volumes of affected cerebral grey matter.The plaques are surrounded by reactive astrocytes and microglia and display swollen distorted neuronal processes (dystrophic neurites). Although detection of plaques is necessary for pathologic diagnosis of AD, their number and distribution do not correlate well with the severity of clinical disease.
NFTs are intracytoplasmic collections of polymerized tau filaments. The tangles are composed of paired, 10 mm thick, helical filaments composed of abundant insoluble tau proteins. Distribution of these tangles correlates with the clinical severity of AD .
AD is both a tauopathy and a β-amyloidopathy characterised by intracellular and extracellular tangles and plaques, respectively, seen in this disorder.
Outline the amyloid pathogenesis of Alzheimer disease. What is the proof Aβ is involved?
β-Amyloid protein (Aβ):Deposition of Aβ protein inneuritic plaquesis always observed in AD. The core of these plaques contains a distinct form of Aβ peptide (42 amino acids long) which is derived by proteolysis from a much larger (695 amino acids) membranespanningAPP. Full-length APP has an extracellular region, a transmembrane sequence and a cytoplasmic domain. The region comprising Aβ anchors the aminoterminal portion of APP to the membrane.
Unlike the normal (nonamyloidgenic) degradation of APP which involves proteolytic cleavage in the middle of the Aβ domain, generation of the amyloidgenic Aβ peptide requires two sequential proteolytic cleavages at either end of the Aβ domain to release an intact and highly amyloidogenic Aβ, which accumulates in senile plaques as amyloid fibrils. Deposition of Aβ necessary:
- Down syndrome patients (t21) develop clinical and pathologic features of AD, including plaques before 40 years (APP gene on ch21- Aβ accumulation).
- Some patients with familial AD carry APP or prenisilin gene mutations, which leads to an increase in Aβ.
- Transgenic mince expressing mutant human APP develop plaques similar to those in AD.
Outline the NFT pathogenesis of Alzheimer disease.
Neurofibrillary tangles: NFTs are composed of paired helical filaments that contain tau (a highly soluble microtubule-associated protein) that is abnormally phosphorylated at aberrant sites. This modification results in a protein that does not associate with microtubules but instead aggregates to form paired helical filaments. Release of tau from microtubules may deprive cells of tau’s microtubule stabilizing effects, thereby impairing axonal transport and compromising neuronal function. Alternatively, fibrils composed of hyperphosphorylated tau aggregates may themselves be cytotoxic.
Outline Parkinson disease (PD).
Parkinson diseas is a major neurodegenerative disorder that affects middle aged-elderly people. It affects 1-3% of the population >65 years, and is characterised by tremors, rigidity, akinesia (difficulty initiating movements), and bradykinesia (slow movements).
Main pathology is the loss of large numbers of dopaminergic neurons in the substantia nigra.
Outline the pathogenesis of Parkinson disease (PD).
Most cases are sporadic, but missense mutations in the α-synucleingene are responsible for rare cases ofautosomal dominant,early-onset,familial PD.
The finding that wild-type α-synuclein is the major polymerized protein in Lewy bodies suggests fibrillogenesis as a major contributor to the pathogenesis of neurodegenerative diseases.
Accumulating evidence suggests that oxidative stress produced by the auto-oxidation of catecholamines during melanin formation injures neurons in the substantia nigra by promoting misfolding of α-synuclein and formation of filamentous inclusions.
Neuronal cell death in PD is likely caused by a combination of toxic protein accumulation and free radical reactions, leading to mitochondrial failure and cell death. In addition to PD, accumulation of filamentous α-synuclein inclusions is seen in a number of other diseases, including multiple system atrophy, dementia with Lewy bodies, progressive autonomic failure, and rapid eye movement (REM) sleep behaviour disorder. These disorders are now called α-synucleinopathies.
How is Parkinson disease (PD) treated?
L-DOPA, which crosses the blood-brain barrier and is converted to dopamine by dopamine-β-carboxylase
Becomes less useful after several years and the majority of patients develop dyskinesia.
Outline Huntington disease (HD).
Huntington disease (HD) is an autosominal dominant single-gene (monogenic) neurodegenerative disorder that affects 1/10,000 people. It has a midlife onset at around 40 years old and the disease has around a 15 year duration.
It is clinically characterised by slow progressive movement disorder, chorea, and eventual dementia.
The main area affected is the basal ganglia of the striatum where neurons are lost. The HD gene was identified on ch4 by positional cloning (1993). A mutation where CAG is expanded causes the disease; normal individuals have 6-34 repeats, whereas HD patient’s have >35 repeats.
The more repeats, the earlier and more severe the onset is.
The expanded CAG (glutamine) repeat causes the toxic Huntington protein to gain function (polyglutamine disorder), causing intranuclear aggregates that destroy cell function.
How is Huntington disease treated?
There is no known treatment.
Investigations are taking place that look into altered polyglutamine protein conformation, transcription dysregulation, and prevention of polyglutamine formation.
Outline Friedrich’s ataxia (FRDA).
FRDA is an autosomal recessive, monogenic, progressive neurological disorder that occurs in 1/30,000 children, with age of onset at 8-15 years old. On chromosome 9.
It leads to ataxia of gait (walking), dysarthria (difficult, unclear speech), and areflexia (below normal/absent reflexes). The primary pathology incolves the large neurons of the dorsal root ganglion, involving sensory nerves and tracts of the spinal cord, causing hypertrophic cardiomyopathy and diabetes mellitus.
