Alzheimer’s disease (AD) is a progressive dementia that primarily impairs memory, language and reasoning. Brains of individuals with AD reduce in size over time and accumulate large quantities of aggregated tau proteins inside the neurons, (neurofibrillary tangles) and extracellular β-amyloid peptides ([AβP] senile plaques).
β-amyloid peptide is produced by β- and γ-secretase enzymes from the amyloid precursor protein, and its aggregation is the focus of intensive studies.
The strongest evidence for amyloid being a cause, and not just a consequence of the disease, comes from genetics. In familial or early-onset forms of AD, mutations in the amyloid precursor protein and the enzymes that clip it to form β-amyloid (Aβ) lead to massive overproduction of Aβ and a swift descent into disease.
The animal models for AD are based on the same premise, that overproduction of the Aβ protein somehow triggers a cascade that eventually damages neurons and causes dementia.
Some of the mice display mutations observed in familial or early-onset AD and form the characteristic plaques seen in diseased brains. Others carry mutations in the protein tau and recreate neurofibrillary tangles, another hallmark of the disease. “In that capacity, the animal models have been extremely successful and that’s no trivial thing”, notes Karen Duff, professor of neuroscience at New York University (NY, USA).
“If amyloid gets so much attention from the scientists, it’s because there’s almost overwhelming evidence that it’s correct fundamentally”, says Harvard neurologist Dennis Selkoe. “Amyloid-β is necessary and it’s very early, and that’s what makes it a beautiful target”.
Does this mean that Aβ is accepted as the primary causative factor in AD pathogenesis and that a therapy will only be successful if it directly targets Aβ aggregation or it resultant neurotoxicity? Indeed, most therapies in trials are aimed at reducing aggregates of the protein. Even if only one of them works, it would lend much needed clinical credibility to the amyloid field.
The amyloid cascade hypothesis, despite its monolithic ring, has under gone some revision. Initially, scientists believed that the plaques themselves were causing the disease. Based on that idea, they proposed that removing the plaques might retard or even reverse the memory loss and cognitive decline seen in AD. Currently, the emphasis is more on oligomers or smaller aggregates of Aβ.
In animal models, both soluble forms of Aβ and fibrillar plaques are implicated in cognitive impairment, but the situation in individuals with AD is more complex. In addition to Aβ-related pathological changes, intraneuronal neurofibrillary lesions and marked neuronal and synaptic losses occur even when people have the earliest clinical symptoms.
Current treatments provide modest symptomatic benefit to some individuals with AD but do little to slow disease progression. At present, there are no disease-modifying therapies available for AD.
AD is a top priority for many major pharmaceutical company portfolio strategies and is actively targeted by many biotechnology companies. Nearly 200 drugs are in development in more than 100 companies, making AD one of the most studied diseases in the pharmaceutical industry.
Drug-development programs in AD focus primarily on agents with anti-amyloid disease-modifying properties and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Acetylcholinesterase inhibitors and memantine are licensed for AD and have moderate symptomatic benefits. Epidemiological studies have suggested that nonsteroidal anti-inflammatory drugs, estrogen, statins or tocopherol (vitamin E) can prevent AD. However, prospective, randomized studies have not convincingly been able to demonstrate clinical efficacy. Major progress in molecular medicine suggests further drug targets. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy, a γ-secretase inhibitor, the selective Aβ-42-lowering agent R-flurbiprofen and the anti-aggregation agent transiposate. Nontraditional dementia therapies, such as the statins, valproate and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary, but not sufficient to demonstrate that a drug has disease-modifying properties. Clinical trials should demonstrate a significantly improved, stabilized or slowed rate of decline in cognitive and global function compared with placebo, as evidenced from surrogate biomarkers that the treatment results in measurable biological changes associated with the underlying disease process.
The anti-Aβ vaccination approach seems to be the most promising at clearing both soluble and deposited forms of amyloid both in mice and in humans who have come to autopsy after the AN1792 trial, but how and whether or not this will influence the function of already devastated neural systems remains to be determined Citation[1].
Whatever the mechanisms involved in Aβ immune activation, it might yet be possible to avoid the unwanted autoreactive immune responses that ended the initial clinical trials. Immunization with fragments of Aβ attached to unrelated carrier molecules may allow a potent humoral immune response to Aβ without activation of T cells against the same peptide.
Alternatively, passive immunization with humanized monoclonal antibodies to Aβ would together eliminate the need for any T-cell response. However, even this may not overcome neuroinflammation associated with immunotherapy, as Pfeifer and colleagues demonstrated cerebral microhemorrhaging was associated with amyloid-laden vessels after passive immunization of mice with antibodies to Aβ Citation[2].
Passive immunization with antibodies devoid of Fc, which may prevent overactivation of microglia and, thus, attenuation of autoantibody-triggered neuroinflammation, may prevent such effects.
Modulation of the inhibitory Fc receptor (FcR) pathway may be an efficient practical therapeutic approach for controlling autoantibody-mediated inflammation induced by self-antigens or antibodies in immunotherapeutic strategies for treatment of AD. One of these is the administration of intravenous immunoglobulin (IVIg), which has well-recognized anti-inflammatory activities independent of the antigen-specific effect. IVIg preparations from several sources contain anti-Aβ peptide antibodies that disaggregate preformed Aβ peptide fibrils in vitroCitation[3].
It has recently been shown that IVIg may interfere directly with Aβ peptide kinetics by dissolving preformed Aβ peptide fibrils. IVIg may also assist microglia in its interaction with β-amyloid peptide, thus enhancing microglial phagocytosis of fibrillar Aβ peptide Citation[3]. Therefore, it is suggested that the modulation of β-amyloid peptide by IVIg therapy and the effectiveness of IVIg in treating AD patients are due to the involvement of a combination of several mechanisms.
Antibodies minimizing interactions with effector molecules, so-called ‘inert’ antibodies, may be another safer alternative for Aβ immunotherapy in the clinic. Deglycosylation of an anti-β-amyloid antibody demonstrated an improved profile with regards to potential adverse effects, suggesting less interaction with Fc-γ receptors or complement components, while maintaining efficacy in reduction of compact amyloid deposits when compared with the intact antibody Citation[4].
Immunotherapy in patients with AD became a hot topic of modern geriatric and clinical gerontology. Current views see immunization with β-amyloid peptide, the amyloidogenic protein found in senile plaque of AD patient’s brains, or the infusion of preformed antibody specific for human β-amyloid, as possible therapeutic approaches to improve the cognitive status in the disease. Animal models of the disease have provided positive results using both approaches.
Why has immunotherapy generally been ignored as a treatment for neurodegenerative disease? Perhaps because vaccination has historically been used to prevent infectious disease, the CNS has traditionally been viewed as an immune-privileged site. These views are now slowly being replaced with the concept that at least some neurodegenerative diseases result from a failure of the immune system to regulate expression of endogenous toxic molecules.
Clearly, despite initial excitement spawned by reports from Schenk and colleagues, and then others, we are still in the early stages of developing immunotherapeutic approaches to treat this devastating illness Citation[5].
Although the vaccine approach is exciting from a scientific perspective, its future as a clinical treatment will depend upon it overcoming the substantial remaining hurdles. Will the vaccine be effective in halting the otherwise inevitable clinical decline of individuals with AD, or even allow improvement? Will new formulations of immunization be safe, or will autoimmune issues always plague this approach of directing the body’s immune system against a normal human protein?
Cautious optimism about the future of AD treatment is warranted, but it will be some time before some of these concerns will be clarified, justifying the optimism by unlocking the immunotherapy potential for the treatment of AD.
References
- Nicholl JAR, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-β-peptide: a case report. Nat. Med.9, 448–452 (2003).
- Pfeifer M, Boncristiano S, Bondolfi L et al. Cerebral hemorrhage after passive anti-Aβ immunotherapy. Science298, 1379 (2002).
- Istrin G, Bosis E, Solomon B. Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-β peptide. J. Neurosci. Res.84(2), 434–443 (2006).
- Carty NC, Wilcock DM, Rosenthal A et al. Intracranial administration of deglycosylated C-terminal-specific anti-Aβ antibody efficiently clears amyloid plaques without activating microglia in amyloid-depositing transgenic mice. J. Neuroinflammation3, 11 (2006).
- Schenk D, Barbour R, Dunn W et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature400(6740), 173–177 (1999).