The trusted source for
healthcare information and
Abstracts & Commentary
Sources: Gotz J, et al. Science. 2001;293:1491-1495; Gouras GK, Beal MF. Neuron. 2001;30:641-642; Nilsberth C, et al. Nat Neurosci. 2001;4:887-893; Lewis J, et al. Science. 2001;293:1487-1491.
Research in the field of neurodegenerative diseases is advancing rapidly. We are reaching the threshold where there appear to be novel insights into both disease mechanisms as well as new therapeutic approaches. There is accumulating evidence for roles of protein aggregation, metabolic dysfunction, and oxidative damage as being central to the pathogenesis of neurodegenerative diseases. In Alzheimer’s disease (AD), there may be direct toxic effects of b-amyloid protofibrils. In the case of Huntington’s disease (HD), there appears to be specific dysfunction of transcriptional regulation. In Parkinson’s disease (PD), there appear to be accumulations of a-synuclein leading to aggregates and impairment of the ubiquitin proteasome system. The latter 2 diseases will be discussed in future issues. These findings provide a number of attractive targets for neuroprotective therapies. The development of transgenic mouse models of neurodegenerative diseases has rapidly accelerated the development of new therapeutic approaches.
In AD the focus has been on the role of beta amyloid (Ab) in disease pathogenesis. This has been particularly strengthened by genetic studies that have demonstrated mutations in the amyloid precursor protein as well, as in the presenilin genes. These are associated with early life-onset familial AD and increased production of Ab 1-42. A recent study, however, has demonstrated that certain mutations in the amyloid precursor protein associates with AD, but results in reduced production of Ab. The latter instance appears to increase the generation of protofibrils. This reflects an intermediate stage of aggregation, which appears to be particularly toxic. These findings suggest that intracellular generation of Ab may play a more direct role in disease pathogenesis, than the extracellular accumulations in senile plaques. Although Ab deposits in senile plaques are closely linked to AD pathogenesis, neurofibrillary tangles are a better pathologic correlate of dementia. Recent work shows that Ab exacerbates neurofibrillary tangles. Administration of Ab or increasing its production in mice with tau mutations, which are associated with frontotemporal degeneration, leads to an exacerbation of the development of neurofibrillary tangle formation.
Several new therapeutic approaches direct their efforts to treat Ab deposition. These include Ab immunization, b and g-secretase inhibitors, modulators of inflammation, antioxidants, and cholesterol lowering drugs. Several groups of investigators have shown Ab immunization to be efficacious. Not only does it reduce the deposition of Ab plaques, it also improves cognitive deficits in transgenic mouse models. This approach has now entered clinical trials. A potential worry about g-secretase inhibition was that it could inhibit notch signaling which could affect the bone marrow. Recent evidence, however, has shown that novel inhibitors can dissociate the 2 effects. Initial trials of g-secretase inhibitors in man have commenced. Development of b-secretase inhibitors appears particularly promising, since b-secretase knockout mice show a normal phenotype, but no Ab generation.
Two epidemiologic studies have shown that patients taking statin drugs have a lower incidence of AD. Studies in the transgenic mouse models of AD have clearly demonstrated that dietary manipulation of cholesterol or statin drugs can markedly reduce Ab generation. Initial trials with statin drugs have started. Studies in the transgenic mice using ibuprofen, as an anti-inflammatory compound, or curcumurin, an antioxidant, have shown significant reductions in Ab levels, development of senile plaques, and in behavioral deficits. A recent study examined the effects of clioquinol, a copper/zinc chelator which was able to solubilize Ab from postmortem AD brain tissue. In transgenic mouse models of AD, administration of this compound is effective in reducing sedimentable Ab as well as in reducing the numbers of amyloid plaques. There are concerns, however, that the compound produces subacute myelo-optic neuropathy, which may be due to vitamin B12 deficiency. Initial clinical trials with clioquinol in combination with vitamin B12 have been completed, and have now entered phase II with reportedly no encounter with myelo-optic neuropathy. A number of approaches for neuroprotection in AD have now entered the clinic, including a number of approaches which will test the primacy of Ab in AD pathogenesis. In the meantime, the best presently available symptomatic therapy is with acetylcholinesterase inhibitors such as donepezil (Aricept), galantamine (Reminyl), and rivastigimine (Exelon). In addition, many practitioners recommend vitamin E, since 1 trial showed slowing of disease progression. —Flint Beal
Dr. Beal is Chairman of Neurology and Neuroscience, Cornell Medical Center, New York Presbyterian Hospital, New York, NY.