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Neurodegenerative Diseases
SIGMA-ALDRICH
Neurodegenerative Diseases
Neurodegenerative diseases are a varied assortment of central nervous system disorders
characterized by neuronal loss and intraneuronal accumulations of fibrillary materials. Abnormal
protein-protein interactions may allow the precipitation of these proteins, forming intracellular and
extracellular aggregates. These abnormal interactions may play a role in the dysfunction and
death of neurons in several common neurodegenerative diseases, such as Alzheimers Disease
(AD) and Parkinsons Disease (PD).
AD is characterized by loss of function and death of nerve cells in the brain leading to loss of
cognitive function. The cause of nerve cell death is unknown but fibrillar b-amyloid senile plaques
(SP) and intraneuronal tau-rich neurofibrillary tangles (NFT) are seen. SP form by the extracellular
accumulation of amyloid beta (Ab) peptide into amyloid deposits, with the Ab 42 form being most
predominant. Proteolytic enzymesb -secretase and g-secretase sequentially cleave the b-amyloid
precursor protein (APP) into Ab. The enzyme BACE (b-site APP Cleaving Enzyme) has been
identified as b-secretase. NFT are made up of aggregated hyperphosphorylated tau protein.
Abnormal phosphorylation, possibly caused by mutations in the tau gene, may be one of the
events leading to aggregation. Common polymorphisms of the apolipoprotein E (ApoE) gene and
risk/age of onset of AD may be linked. The ApoE4 gene seems to carry more risk for an earlier
onset of AD; the ApoE2 gene appears to be somewhat protective. ApoE can bind to both SP and
NFT.
PD is a slowly progressing, degenerative disease characterized by resting tremor, expressionless
face, rigidity and slowness in initiating and performing voluntary movements. Neuropathologically,
PD is characterized by loss of dopaminergic cell bodies in the substantia nigra, resulting in a
reduced supply of dopamine in the basal ganglia. Intracellular inclusions called Lewy bodies,
consisting of a-synuclein protein, are also seen. Mutations of the a-synuclein gene may cause the
dominantly inherited Lewy-Body Parkinsons disease. The cause of the more common form of PD
(multifactorial) is unknown, although it may be associated with oxidative stress and derangements
in mitochondrial complex I activity.