CNS & Neurological Disorders - Drug Targets - Volume 8, Issue 2, 2009

Alzheimer's disease (AD) is the leading cause of dementia among older people. An estimated 10% of Americans over the age of 65 and half of those over age 85 have Alzheimer's. More than four million Americans currently suffer from the disease, and the number is projected to balloon to 10-15 million over the next several decades. Alzheimer's is now the third most expensive disease to treat in the U.S., costing society close to $100 billion annually [1]. The clinical criteria for the diagnosis of AD include insidious onset and progressive impairment of memory and other cognitive functions; however a definitive diagnosis of AD can currently be made only at autopsy by examining brain tissue for amyloid plaques and neurofibrillary tangles. The extracellular amyloid plaques and intracellular neurofibrillary tangles represent examples of proteinopathies or proteopathies, which result from aberrant accumulation of misfolded or aggregated proteins that are believed to interfere with normal functions, and thereby either directly or indirectly contribute to disease pathogenesis. In addition to AD, misfolding or aberrant aggregation of proteins are central features of other neurodegenerative diseases as well, including tauopathies, Parkinson disease, amyotrophic lateral sclerosis, prion diseases, and the polyglutamine (polygln) diseases [2, 3]. Therapeutic strategies targeted at this class of diseases have focused on three areas: 1) reducing the production of the protein/peptide; 2) blocking the assembly of aberrant forms; or 3) promoting clearance [4].

Post mortem examinations of AN-1792-vaccinated humans revealed this therapy produced focal senile plaque disruption. Despite the dispersal of substantial plaque material, vaccination did not constitute even a partial eradication of brain amyloid as water soluble amyloid-β (Aβ) 40/42 increased in the gray matter compared to sporadic Alzheimer's disease (AD) patients and total brain Aβ levels were not decreased. Significant aspects of AD pathology were unaffected by vaccination with both vascular amyloid and hyperphosphorylated tau deposits appeared refractory to this therapy. In addition, vaccination resulted in the consequential and drastic expansion of the white matter (WM) amyloid pool to levels without precedent in sporadic AD patients. Although vaccination disrupted amyloid plaques, this therapy did not enhance long-term cognitive function or necessarily halt neurodegeneration. The intricate involvement of vascular pathology in AD evolution and the firm recalcitrance of vessel-associated amyloid to antibody-mediated disruption suggest that immunization therapies might be more effective if administered on a prophylactic basis before vascular impairment and well ahead of any clinically evident cognitive decline. Amyloid-β is viewed as pathological based on the postmortem correlation of senile plaques with an AD diagnosis. It remains uncertain which of the various forms of this peptide is the most toxic and whether Aβ or senile plaques themselves serve any desirable or protective functions. The long-term cognitive effects of chronic immunotherapy producing a steadily accumulating and effectively permanent pool of disrupted Aβ peptides within the human brain are unknown. In addition, the side effects of such therapy provided on a chronic basis could extend far beyond the brain. Eagerly seeking new therapies, critical knowledge gaps should prompt us to take a more wholistic perspective viewing Aβ and the amyloid cascade as aspects of complex and many-faceted physiological processes that sometimes end in AD dementia.

Alzheimer disease (AD) is the most common form of dementia in the elderly and the number of individuals developing the disease is rapidly rising. Interventions focused on reducing beta-amyloid (Aβ), a component of senile plaques within the AD brain offer a promising approach to prevent or slow disease progression. In this review, we describe the immune system and cognitive and neurobiological features of a natural model of human brain aging, the beagle. The immune system of dogs shares many features of the human immune system, including developmental and aging characteristics. Further, dogs naturally accumulate human sequence Aβ as they age, which coincides with declines in learning and memory. A longitudinal study (∼2 years) of the response of aged beagles to vaccination with fibrillar Aβ1-42 indicated that despite significant clearance of Aβ, there were limited benefits in cognitive function. However, there was evidence for maintenance of executive function over time. These results are strikingly similar to reports of human clinical immunotherapy trials. We propose that the canine model complements existing animal models and will be helpful in developing new vaccine approaches to slowing or preventing Aβ pathology that can be translated to human clinical trials.

In a seminal report in 1999, Schenk and colleagues demonstrated that vaccination of a mouse model of Alzheimer's disease (AD) with amyloid-β1-42 peptide (Aβ1-42) and adjuvant resulted in striking mitigation of AD-like pathology - giving rise to the field of AD immunotherapy. Later studies confirmed this result in other mouse models of AD and additionally showed cognitive improvement after Aβ vaccination. Based on these results, early developmental clinical trials ensued to immunize AD patients with Aβ1-42 plus adjuvant (so-called “active” Aβ immunotherapy; trade name AN-1792; Elan Pharmaceuticals, Dublin, Ireland). However, the phase IIa trial was halted after 6 % of patients developed aseptic meningoencephalitis. Despite occurrence of this adverse event, many individuals demonstrated high serum antibody titres to Aβ and histological evidence of clearance of the hallmark AD pathology, β-amyloid plaques. While raising justifiable safety concerns, these important results nonetheless demonstrated the feasibility of the active Aβ immunotherapy approach. This review focuses on alternative approaches to active Aβ vaccination that are currently in various stages of development - from pre-clinical studies in animal models to current clinical trials. Specifically, the focus is on those strategies that target inflammatory and immune aspects of AD, and can therefore be classified as immunotherapeutic in a broad sense.

Amyloid-beta (Aβ) immunotherapy has received considerable attention as a promising approach for reducing the level of Aβ in the CNS of Alzheimer's disease patients. However, the first Phase II clinical trial, for the immune therapy AN1792, was halted when a subset of those immunized with Aβ42 developed adverse events in the central nervous system. In addition, data from the trial indicated that there was a low percentage of responders and generally low to moderate titers in the patients that received the vaccine. Generated antibodies reduced β-amyloid deposits in the parenchyma of patients' brains, but no reduction in soluble Aβ or significant improvements in cognitive function of patients were observed. These data and data from pre-clinical studies suggest that reduction in the most toxic oligomeric forms of Aβ is important for prevention or slowing down of the progression of cognitive decline, and that vaccination should be started prior to irreversible accumulation of the oligomeric Aβ, at the early stages of AD. Protective immunotherapy requires a development of safe and effective strategy for Aβ immunotherapy. In this review, the rationale for developing epitope vaccines for the treatment of AD will be discussed. We believe that an epitope vaccine will induce an adequate anti-Aβ antibody response in the absence of potentially adverse self T cell-mediated events, making it possible to start immunization at the early stages of AD.

Over the last 10 years, promising data has emerged from both animal and human studies that both active immunization with amyloid-β (Aβ) as well as passive immunization with anti-Aβ antibodies offer promise as therapies for Alzheimer's disease (AD). Data from animal models suggests that antibodies to Aβ through several mechanisms can decrease Aβ deposition, decrease Aβ -associated damage such as dystrophic neurite formation, and improve behavioral performance. Data from human studies suggests that active immunization can result in plaque clearance and that passive immunotherapy might result in slowing of cognitive decline. Despite this, a recent analysis from a phase I trial that involved active immunization with Aβ42, while not powered to determine efficacy, suggested no large effect of active immunization despite the fact that plaque clearance was very prominent in some subjects. An important issue to consider is when active or passive immunization targeting Aβ has the chance to be most effective. Clinico-pathological and biomarker studies have shown that in terms of the time course of AD, Aβ deposition probably begins about 10-15 years prior to symptom onset (preclinical AD) and that tau aggregation in tangles and in neurites does not begin to accelerate and build up in larger amounts in the neocortex until just prior to symptom onset. By the time the earliest clinical signs of AD emerge, Aβ deposition may be close to reaching its peak and tangle formation and neuronal cell loss is substantial though still not at its maximal extent. Since immunization targeting Aβ does not appear to have major effects on tangle pathology, for immunization to have the most chance for success, performing clinical trials in individuals who are cognitively only very mildly impaired or even in those with preclinical AD would likely offer a much better chance for success. Current work with AD biomarkers suggests that such individuals can now be identified and it seems likely that targeting this population with immunization strategies targeting Aβ would offer the best chance of success.

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