Neurones within the brains of patients with neurodegenerative disorders often show intracellular inclusions, many of which seem to consist of abnormal molecules derived from normal components of the neurone, including misfolded proteins. These include the neurofibrillary tangles in Alzheimer's Disease and Lewy Bodies in Parkinson's Disease, and nuclear inclusions in neurones of patients with Huntington's Disease.
In addition there is an accumulation of extracellular insoluble beta-amyloid in Alzheimer's Disease. Amyloid Protein Precursor (APP) is a normal protein in many neurones, but in Alzheimer's Disease, an insoluble polymer called beta-amyloid accumulates OUTSIDE the neurone, and contributes of neuronal degeneration.
Normally, the initial cleavage of APP is by an enzyme, alpha-secretase, and the product is sufficiently souble to be removed. Some authors believe that beta-amyloid is produced by the enzyme beta-secretase (BACE1), and the product is able to polymerise and become an insoluble form of amyloid protein (beta-Amyloid).
It is interesting that not all types of neurones are equally affected by Alzheimer's disease, which begs the question of how neurones are involved in the development of plaques of insoluble beta-amyloid.
In all of these pathological changes there is evidence of misfolding of proteins.
Neurofibrillary tangles appear to be an aggregation of a misfolded form of tau protein, a normal component of neurotubules. Alpha-synuclein is another protein, present in normal neurones, that can accumulate in degenerating nerve cells, particularly in association with Lewy Bodies in Parkinson's Disease. Some authors believe that these inclusions disrupt axonal transport, which results in a lack of chemical communication between the cell body and the axonal terminal and a consequent inability to sustain the terminal and synaptic transmission.