Molecular Mass

The reason why developmental abnormalities occur in SLOS has not been completely elucidated.Some intriguing similarities have been noted, however, between NPC disease and AD.For example, both diseases exhibit endosomal andor lysosomal abnormalities.Furthermore, neurofibrillary tangles containing hyperphosphorylated tau are abundant in the brains of individuals with either NPC disease or AD. However, despite the wellestablished association between APOE and AD, a molecular mechanism that directly connects cholesterol metabolism with the neurological impairments of AD is lacking.Indeed, it is possible that the observed defects in cholesterol metabolism in AD are the consequence, rather than the cause, of the disease.In HD, cholesterol metabolism is clearly altered in neurons expressing mutant huntingtin, but any causal link between cholesterol imbalance and the neurodegeneration that is characteristic of this disease is tenuous.A clear link has also not been established between cholesterol metabolism and the neurodegenerative phenotype of PD, although in vitro experiments indicate that high levels of cholesterol promote the {|Targetmol’s {Endurobol|Amiodarone aggregation of synuclein.An interesting point to consider when comparing cholesterol metabolism in these neurodegenerative diseases is the region of the brain that is primarily affected.AD, HD and PD are also characterized by the loss of neurons from distinct regions of the brain.In AD, the neurons that fail to survive are primarily in the hippocampus, whereas in HD the survival of striatal neurons is most severely impaired and in PD the dopaminergic neurons in the substantia nigra are the most affected.These observations raise the question of whether there are fundamental differences in the mechanisms that link cholesterol homeostasis and neuronal survival in these different types of neurons.More information is clearly required to determine whether the neurodegenerative phenotype of these diseases can be attributed to impaired cholesterol metabolism.Nevertheless, possible therapeutic strategies for altering cholesterol metabolism in the brains of individuals suffering from these diseases are currently being considered.As discussed above, the prospect of delivering cyclodextrin intrathecally for the treatment of individuals with NPC disease is very promising, but this would be a drastic treatment.It is unlikely that this agent would be useful for treating any of the other diseases discussed above.Furthermore, whether any of the potential benefits of the statins for treatment of AD, and perhaps also of PD, are due to their cholesterollowering effects or to their antiinf lammatory or antioxidant properties remains to be determined.If the statins proved beneficial for AD andor PD, use of only the class of statins that can cross the bloodbrain barrier would be indicated.Indeed, an important consideration when devising therapeutic strategies that target any metabolic pathway in the brain is that many molecules do not freely cross the bloodbrain barrier.Thus, delivery of a drug into the brain is often problematic, as is the use of gene therapy for neurodegenerative diseases. Another problem in devising treatments for neurodegenerative diseases is the difficulty of reversing brain damage that has already occurred.Many of the questions raised above should stimulate research questions regarding the fundamental molecular mechanisms that regulate cholesterol homeostasis in different types of cells in the brain, and determine how alterations in cholesterol balance affect the survival and function of neurons and glial cells.

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