Prions and Alzheimers disease
Industrialized societies are in the middle of an epidemic in which the killers of youth are being replaced by the killers of old age. Among the most disturbing of these new threats are a set of degenerative brain diseases known as the amyloidoses. A number of different conditions are characterized by strange protein deposits in various organs of the body. These abnormal or “amyloid” deposits consist of accumulations of many different proteins in the form of spherical plaques or thin fibrils, depending on their origin. Scientists and doctors do not understand exactly how and why proteins become locked up in these deposits, except that the normal mechanisms which keep vigorous, healthy cells free of this accumulated junk must somehow become damaged or blocked.
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The underlying pathology in Alzheimer’s disease is caused by the presence of extracellular senile plaques and intracellular tangles within the brains of affected people. The major component of these structures are amyloid peptides, which are derived from the proteolytic processing of the amyloid precursor protein (APP).
More than 5 million Americans are estimated to have Alzheimer’s disease, and it was the 7th leading cause of death in the USA in 2004 with nearly 66,000 diagnosed deaths. It is predicted that 14.3 million Americans will have the disease by the middle of this century. In the UK, Alzheimer’s disease affects over 400,000 people and the number of diagnoses is growing year by year.
If you’re a regular reader of MicrobiologyBytes, you may know that the prion protein (PrP) is the causative agent of the transmissible spongiform encephalopathies (TSEs). These include Creutzfeldt–Jakob disease (CJD) and other conditions in humans, bovine spongiform encephalopathy (BSE or mad cow disease) in cattle, and scrapie in sheep. In these so-called prion diseases, the normal cellular form of PrP (PrPc) undergoes a conformational change to the infectious form of the protein, PrPSc. In spite of extensive studies, the normal cellular function of PrPc remains unknown, but it has been proposed to have various roles in metal homeostasis, neuroprotective signaling, and the cellular response to oxidative stress. Interestingly, Alzheimer’s disease and CJD share a variety of neuropathological features, and the Val/Met polymorphism at residue 129 in the gene encoding PrPc has been identified as a risk factor for the early onset of Alzheimer’s disease.
A recent paper in PNAS investigated whether PrPc alters the proteolytic processing of APP and so might lead to the formation of amyloid plaques (Cellular prion protein regulates beta-secretase cleavage of the Alzheimer’s amyloid precursor protein.
PNAS USA 2007 104: 11062-11067). Over expression of PrPc inhibited cleavage of APP and reduced amyloid formation. Conversely, depletion of PrPc in mouse cells by siRNA led to an increase in amyloid peptides secreted into the medium. In the brains of PrP knockout mice and in brains from scrapie-infected mice, amyloid levels were also significantly increased. Using constructs which expressed PrP, the researchers demonstrated that the regulatory effect of PrPc on the cleavage of APP required the localization of PrPc to cholesterol-rich lipid rafts in cell membranes.
The authors suggest it is conceivable that small changes in PrPc levels in individuals may affect proteolytic processing of APP in a subtle way over many decades to affect long-term amyloid production, which in turn could either accelerate or decelerate the deposition of amyloid in the brain. Whether this function is lost as a result of the normal ageing process, or if some people are more susceptible than others is not yet known.
In spite of their biochemical similarities, this is the first time a definite link has been made between PrP and Alzheimer’s disease. Ultimately, this could provide the foundations for novel approaches to finding new therapeutic targets in Alzheimer’s. But while this represents an advance in understanding Alzheimer’s disease, these observations also raise significant questions over whether depletion of PrPc is a sound therapeutic approach for prion diseases.
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Data from the study, the largest of its kind, contradicts some previous studies that found that ibuprofen might exceed others in its class when it comes to preventing this type of dementia. Besides ibuprofen, other types of NSAIDs include naproxen and aspirin.
But the bottom line, the study authors said, is that the findings don’t support the use of NSAIDs to prevent or treat Alzheimer’s, at least not yet anyway.