Faculty Bibliography

To date, transmissibility of amyloid diseases has not been thoroughly investigated. Although only some of these conformational disorders are considered infectious, all amyloid diseases could be infectious under certain conditions. For transmissibility, endogenous expression of an amyloidogenic peptide required, as well as the presence of an inoculum that is rich in amyloid fibrils and/or their precursors. Notably, administration of one type of amyloid might result in deposition of a different amyloid. Various cofactors could be essential for transmission - some might chaperone the amyloid peptides and/or fibrils, thereby directly facilitating their propagation; others might indirectly stabilize and/or increase levels of conformers with a high beta-sheet content. It is possible that these chaperones are induced by inflammation, which itself can lead to secondary amyloidosis. Thus, amyloid-related therapeutic approaches should not be based on administration of amyloidogenic peptides in conjunction with an inflammatory stimulus, such as in a recently halted clinical trial for Alzheimer's disease

There is growing realization that many neurodegenerative conditions have the same underlying pathogenetic mechanism: a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease (AD), amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid beta (sAbeta) to Abeta plaques, whereas in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. Different approaches under development include drugs that affect the processing of the precursor proteins, enhance clearance of the amyloidogenic protein, and inhibit or prevent the conformation change. Particularly interesting are recent studies of immune system activation, which appear to increase the clearance of the disease-associated protein. These immunologically based approaches are highly effective in animal models of these disorders, and in these model systems are associated with no obvious side effects. In transgenic mice with AD-related pathology, immunization has also been shown to prevent age-related cognitive impairment. However, the first clinical trial of this approach in AD patients was associated with unacceptable toxicity. These immune-based treatment approaches have great potential as rational therapies for this devastating group of disorders, but additional development is needed before they can be safely applied to humans

There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease, amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid-beta peptide (sA beta) to A beta plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to the disease-associated form, PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. A number of different approaches under current development include drugs which affect the processing of the precursor proteins drugs the clearance of the amyloidogenic protein, and which inhibit or prevent the conformation change and immunological approaches. Particularly interesting are compounds termed 'beta-sheet breakers' that directly target the abnormal conformational change both for A beta- and PrP(Sc)-related deposits. In addition, immune system activation can serve as beta-sheet breakers and/or to increase the clearance of the disease-associated proteins. These conformation-based approaches appear to hold the best promise for therapies for this devastating group of disorders

The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially large population being at risk to develop this prionosis. None of the prionoses currently have an effective treatment. Recently, vaccination has been shown to be effective in mouse models of another neurodegenerative condition, namely Alzheimer's disease. Here we report that vaccination with recombinant mouse prion protein delays the onset of prion disease in mice. Vaccination was performed both before peripheral prion exposure and after exposure. A delay in disease onset was seen in both groups, but was more prolonged in animals immunized before exposure. The increase in the incubation period closely correlated with the anti-prion protein antibody titer. This promising finding suggests that a similar approach may work in humans or other mammalian species at risk for prion disease

The recent termination of a Phase II clinical trial in which volunteers with Alzheimer's disease (AD) were vaccinated with Amyloid-beta (AP)1-42, has cast doubt on the feasibility of this therapeutic approach. While the exact reasons for the cerebral inflammation in these patients is being determined, it is difficult to evaluate the cause of these adverse effects. The most likely reasons are Abeta1-42 toxicity and/or autoimmunity. Abeta vaccination approaches are based on the hypothesis that Abeta deposition and toxicity are central to the pathogenesis of AD. Therefore, it is counterintuitive to use the whole Abeta peptide for human vaccination. Abeta1-40/42 is a major plaque component that forms inflammatory/toxic fibrils as observed in many in vitro and in vivo studies. Furthermore, numerous studies have shown that Abeta1-40/42 bidirectionally crosses the blood-brain barrier (BBB) in experimental animals. Additionally, in vitro and in vivo studies indicate that minute amounts of Abeta1-42 may seed fibril/amyloid formation. The elderly, a target population for AD therapy, often have a poor immune response to vaccines, which enhances the gravity of these safety concerns. In these patients with an attenuated immune reaction, injected Abeta1-42 may initiate and/or enhance congophilic angiopathy, which eventually may result in reduced cerebral blood flow and/or intracerebral bleeding. Abeta1-42 may also cross the BBB and once within the brain parenchyma it may contribute to plaque formation and/or co-deposit on plaques. Together, these effects within blood vessels and/or brain parenchyma may actually enhance the progression of AD. Given the potential serious side effects of Abeta1-42 vaccination, it is safer to use immunogenic Abeta derivatives, which are less likely to be toxic. The main immunogenic epitopes of Abeta1-42 are contained within the first 30 amino acids of the peptide. Taking this into account, we have developed soluble antigenic Abeta derivatives, which are nonfibrillogenic and nontoxic in human cell culture. Our prototype peptide, K6Abeta1-30-NHz, diminishes amyloid burden to a similar extent as reported for Abeta1-42. Additionally, ramified IL-1beta-positive microglia as well as phagocytes, associated with the Abeta plaques, were absent in the immunized mice, indicating reduced inflammation in these animals at the time point examined. Autoimmunity may be the culprit if follow-up studies reveal that the brain inflammation is related to antibody interactions with AD and/or amyloid precursor protein (APP). In such a scenario, any vaccination approach targeting A(3 can have similar consequences, although preventive treatment initiated prior to amyloid deposition may not result in these adverse reactions. T-cell-related autoimmunity may also be involved and can be expected to be less with Abeta derivatives not containing certain T-cell epitopes. An alternative to the active vaccination approach is passive immunization, which is associated with a lower risk of irreversible autoimmunity. This approach may also be used in patients with a muted immune response to the vaccine. However, in a chronic disease such as AD repeated antibody injections may lead to an anti-idiotype response and the resulting serum immune complexes can cause vasculitis and/or glomerulonephritis. Reduction of soluble Abeta within the peripheral system may be a critical part of the pathway that reduces cerebral plaque burden in Tg mice and ultimately in AD patients. Overall, the use of nontoxic A(3 derivatives and/or antibodies with very limited access into the CNS, such as IgM, may prove to have reduced si Any therapeutic approach will be more effective when used prophylactically because of neuronal loss and increased amyloid burden in the later stages of AD. Reversal of clinical symptoms cannot be expected and early diagnosis of AD may be needed for effective therapy. (C) 2002 Wiley-Liss, Inc