Neurodegenerative Diseases are diseases that result in the progressive death of neurones, and include Alzheimer's, Huntington's and Parkinson's diseases, Motoneurone disease and others.
They are characterised by the presence of intracellular inclusion bodies, including
the intranuclear inclusion bodies of Huntington's Disease.
In Alzheimer's disease there are also extracellular accumulations of beta amyloid. Dementia with Lewy bodies (DLB) is a type of dementia that shares symptoms with both Alzheimer's disease and Parkinson's disease.
Chronic repeated trauma to the brain, as occurs in some sports, also results in abnormal intracellular protein aggregates. Dementia is common in all these conditions.
Misfolded protein aggregates appear to be an intrinsic part of the pathology of beta-amyloid and Lewy Bodies. Two proteins, Amyloid Precursor Protein and Synuclein Cells are present in normal cells, but are involved in the formation of beta-Amyloid and Lewy Bodies by abnormal folding of their protein chains.
In nerve cells, the mechanism for handling old and abnormal proteins depends on retrograde axoplasmic transport, and misfolded proteins are transported to a peri-nuclear location, the site where Lewy bodies develop in neurodegenerative disorders such as Parkinson's Disease. If retrograde axoplasmic transport fails, misfolded proteins accumulate , and this may be the mechanism for formation of neurofibrillary tangles
Some proteins, such as beta-amyloid and synuclein, accumulate in parts of the brain. While a number of pathophysiological processes contribute to the development of these conditions, it is known that normal neurotubules have an important role in the clearance of beta-amyloid from axons.
Studies of animals with mad cow disease (bovine spongiform encephalopathy) have led to a concept of prion disease, in which the presence of an abnormal misfolded protein can cause normal proteins, synthesised by the neurone, to adopt an abnormal structure, which then accumulates and causes neurodegeneration. This mechanism may operate more generally in the formation of abnormal protein aggregates.
There is some evidence that protein aggregates can be passed from cell to cell, which may explain why the degeneration process can spread widely within the brain in Alzheimer's Disease.
Comparison of normal and Alzheimer brains: not the atrophy in Alzheimer's Diseases due to loss of cortical neurones.
Neurodegenerative Diseases are diseases that result in the progressive death of neurones, and consequently shrinkage of the brain tissue involved.
Neurones within the brain of patients with neurodegenerative disorders often show intracellular inclusions, many of which consist of abnormal misfolded proteins derived from normal components of the neurone.
Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Motoneurone Disease involve intracellular pathology within neurones in the cerebral cortex, the substantial nigra, the basal ganglia and motoneurones respectively. These changes culminate in neuronal cell death in these areas, and symptoms in common with other disorders of these structures.
In Alzheimer's disease, intracellular neurofibrillary tangles and extracellular insoluble beta-amyloid characterise the neuronal pathology in the cerebral cortex. Alzheimer's patients have dementia with progressive memory loss and difficulties with thinking, problem-solving or language.
In Parkinson's Disease neurones in the substantia nigra develop intracellular inclusions (Lewy Bodies) containing aggregates of synuclein, and lose their capacity to produce their neurotransmitter dopamine.
The nuclei of basal ganglia neurones from patients with Huntington's Disease contain characteristic inclusion bodies consisting of aggregates of an abnormal Huntingtin protein. This inherited disease is characterised by disorders of movement.
In Motoneurone Disease and Amyotrophic Lateral Sclerosis (ALS) upper and lower motoneurones degenerate causing paralysis and wasting of skeletal muscles. Intracellular inclusions are present in affected neurones, and are given a variety of names; some have abnormalities of synuclein (commonly associated with Lewy Bodies).
Neuronal Changes in Neurodegenerative Disorders
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The histological picture shows the presence of beta-amyloid in Alzheimer's Disease
Insoluble beta-amyloid accumulates in the brains of patients with Alzheimer's Disease.
Amyloid precursor protein (APP) is a highly conserved membrane protein that is expressed in many tissues and particularly at synapses.
APP is the precursor of beta amyloid (Aβ), a small peptide that polymerises to produce amyloid plaques in the brains of Alzheimer's disease patients.
Three secretase enzymes are involved in cutting the APP molecule in different sites to produce β-amyloid. If alpha secretase does not divide APP at the normal site, the actions of beta and gamma secretases produce β-amyloid peptides containing 40 or 42 amino acids. These polymerise to form insoluble toxic plaques; this is probably due to a mis-folding of the tertiary structure of the protein.
Normally, misfolded proteins are removed form distant parts of the neurone by retrograde axoplasmic transport, and are caged within aggresomes in the cell body for disposal.
Image source: Nature Reviews
The relationship between tau protein and microtubules, and the formation of neurofibrillary tangles.
Beta tubulin and tau protein: involvement in neurofibrillary tangles.
The cytoarchiteture of neurones is composed of neurotubules and neurofilaments.
Neurotubules are the microtubules of nerve cells and extend throughout the cell body and axon; they are the track along which materials are moved between the cell body and the axon terminals using axonal transport.
Neurotubules consist of a a polymer of alpha and beta tubulin, which are normally organized in orderly parallel strands, being linked together by microtubule associated proteins including one called tau.
Normal tau-containing neurotubules are organized in orderly parallel strands which form the tracks along which molecular motors carry materials to and from the nerve terminals. tau helps the tracks stay straight.
tau is part of the attachment mechanism of the molecular motors, kinesin and dynein that mediate anterograde and retrograde transport respectively.
The materials carried include the enzyme BACE-1 and its product, beta-amyloid. It is believed that axoplasmic transport can remove beta-amyloid, but when tangles are formed this clearance is no longer effective.
In Alzheimer's disease, the normal arrangement of tau and the tubulins collapses: the neurotubules, the track used for axoplasmic transport, are no longer straight, and form neurofibrillary tangles; as a result the movement of materials within the neurone is disrupted.
An abnormal additional phoshorylation of tau is believed to be part of the process whereby the structural stability of neurotubules is disturbed, resulting in the formation of neurofibrillary tangles, which contain a number of proteins including tau.
Composition of Lewy Bodies?
Image source: www.alzheimerstreatment.link
Lewy Body in the cortex of a patient with Lewy body dementia. Lewy bodies are cytoplasmic inclusion bodies situated near the cell nucleus, and are closely associated with the centrosome, a central point in the cell to which microtubules/neurotubules are anchored.
Lewy bodies occur in the midbrain of patients with Parkinson's disease, and in the cortex of patients with Lewy-body Dementia
Many cell functions are threatened by the presence of misfolded proteins that consequently cannot perform their normal functions; cells have evolved systems that protect them from these failures.
One of the main mechanisms involves the formation of aggresomes - aggregations of misfolded proteins that are carried along the microtubules to a site near the nucleus where intracellular inclusions are formed.
Aggresomes consist of a cage made of a protein, vimentin, surrounding a core of aggregated protein, such as alpha-synuclein, and these aggresomes appear to become the Lewy bodies of Parkinson's Disease.
Lewy bodies typically have an eosinophilic core surrounded by a halo of fibrils, consisting of alpha-synuclein.
Other associated proteins include ubiquitin, neurofilament protein, alpha B crystallin and tau.
Image source: Wikipedia
Misfolded protein (red) combines with the normally folded protein produced by the neurone, and alters its stucture to the misfolded confomation. The red molecules proliferate and continue the process. This mechanism is proposed for the replication of misfolded proteins in bovine spongiform encephalopathy, and may be a model for the accumulation of misfolded proteins in other disorders.
The term Prion stands for PRotein InfectiON, as the protein seems to be able to reproduce, but using a quite different mechanism from other infectioous agents, such as bacteria or viruses.
Prion protein (PrP) is a normal constituent of many neurones and can fold in a number of different distinct ways.
If a misfolded prion enters a healthy organism, it can act as a template that induces existing, properly folded proteins to adopt the shape of the misfolded prion. The misfolded protein is insoluble and appears as a particle in histological sections.
The prion mechanism was proposed as a result of studies of bovine spongiform encephalopathy (mad cow disease).
Image source: www.icms.qmul.ac.uk
The diagram shows the main features that distinguish necrosis and apoptosis.
can occur by a number of processes, including necrosis and apoptosis.
Necrosis is the process where ischaemia, infection or toxins cause the death of many cells of different
types in a particular location.
Excitotoxic cell death occurs when the cell fills with calcium ions as a result of
overexcitation with glutamate, as occurs in neurological trauma or
ischaemia. Calcium ions active various enzymes that damage the
cytoskeleton, cell membrane and DNA, and lead to necrosis
Apoptosis is the physiological process of programmed cell death that
affects cells individually. It has a characteristic sequence of biochemical
and anatomical changes resulting in cell death.
Apoptosis is initated by a family of
enzymes called caspases.
Apoptosis is common during neural development, when it removes roughly 50% of the neurones produced in the embryonic CNS.
Apoptosis has been found in neurones, astrocytes and oligdendrocytes.