The utility of vaccine strategies to treat neurodegenerative diseases such as Alzheimer's disease (AD) may still hold promise. Both active and passive immunization strategies reduced AD-like pathology and restored cognitive deficits in transgenic mice. These results were initially met with considerable optimism; however, phase IIa clinical trials were halted because of a small but significant occurrence of meningoencephalitis. Knowledge gained from studies on amyloid- peptide (A) immunotherapy will allow optimization of new-generation vaccines, targeting highly specific epitopes while reducing undesired side effects. In harnessing and steering the immune system, an effective response can be generated against A. If this proves successful, A vaccination could provide the first definitive treatment for AD.
Alzheimer's disease (AD) is the most common cause of age-related cognitive decline, affecting Ͼ12 million people worldwide (1). The disease is characterized in its earlier stages by progressive memory impairment and cognitive decline, altered behavior, and language deficits. Later, patients present with global amnesia and slowing of motor functions, with death typically occurring within 9 years after diagnosis (2). Current drug therapy aims at slowing cognitive decline and ameliorating the affective and behavioral symptoms associated with disease progression. However, these drugs provide limited symptomatic treatment, without targeting the underlying cause of AD. Immunization of AD patients provides a novel means of specifically targeting the neurotoxic effects of amyloid- peptide (A) and thereby targeting disease progression.
The Amyloid Cascade HypothesisThe main constituent of amyloid consists of a 40-to 43-aa peptide, A, and is derived from the proteolytic cleavage of a family of ubiquitously expressed membrane-spanning proteins, termed the amyloid precursor proteins (APP) (3). Under normal conditions, the most abundant species in the brain is the A (1-40) peptide (A 40 ); however, much of the fibrillar A is composed of the longer, more fibrillogenic A (1-42) peptide (A 42 ) (3). These normally soluble peptides undergo conformational change and polymerize into an aggregated and toxic form, rich in -structure (4). Initially, A 42 is deposited in an immature, diffuse (nonfibrillar) plaque, with little or no detectable neuritic dystrophy.Early studies have shown that synthetic fibrillar forms of A are toxic to cultured neurons (5-7). Several mechanisms of A-induced neurotoxicity have been proposed, including oxidative stress, free-radical formation, disrupted calcium homeostasis, induction of apoptosis, chronic inflammation, and activation of complement (8). Although it has been shown that increased levels of A in the brain correlate with cognitive decline (9), relatively weak correlations exist between fibrillar amyloid plaque density and severity of dementia (10-12). Recent studies point to other forms of A, namely, small oligomers as the neurotoxic species (13,14).Recent reports using antibo...
