Immunotherapy for Alzheimer's disease

Abstract

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...

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

“…The molecular mechanisms by which antibodies act in a therapeutic manner are just beginning to be understood (for recent reviews see [94][95][96][97][98][99]) (Textbox 3). The favourable results with animal models led to an initial clinical trial, in which AD patients were injected with samples of aggregated Ab-peptide to elicit an immune response.…”

“…The mechanisms underlying the potentially adverse effects of amyloid immunotherapy are being very actively investigated and extensive research is under way to develop new vaccination strategies to enable beneficial effects to be achieved without undesirable side effects (for reviews see [94][95][96][97][98][99]104,105]). Passive immunisation with antibodies with predetermined effects on amyloid fibril formation/ clearance and toxicity represents an alternative strategy to avoid the potentially damaging side effects of active immunisation [95,96,99,104,105]. Sequences corresponding of the paratope (i.e.…”

“…Moreover, intensive research is being carried out to understand the mechanism of action of antibodies directed against amyloid fibrils or their precursors in vivo. Despite the side effects observed in the recent trial of human Ab immunisation, passive and even active immunisation against a wide range of protein misfolding diseases are undoubtedly highly promising therapeutic strategies that could result in effective clinical treatment in the not-too-distant future [94][95][96][97][98][99].…”

Application of Surface-Enhanced Raman Spectroscopy for Detection of Beta Amyloid Using Nanoshells

“…With an annual cost of over $100 billion per year, AD is the third most costly disease in the USA after heart disease and cancer [6]. In recent years, there has been great interest and progress made in the development of molecular level strategies to target steps in the pathogenesis of AD [7][8][9][10][11][12][13][14][15][16][17][18], with the expectation that even a modest delay of onset of AD of as little as 5 years would result in a 50% reduction in the number of AD patients [19]. However, if these new molecular therapeutics are to be successfully applied, a definitive premortem diagnosis of AD is necessary.…”

Nasal inoculation of an adenovirus vector encoding 11 tandem repeats of Aβ1‐6 upregulates IL‐10 expression and reduces amyloid load in a Mo/Hu APPswe PS1dE9 mouse model of Alzheimer's disease

“…Peripheral administration of antibodies against Aβ also induced clearance of preexisting amyloid plaques in an AD mouse model [20], indicating that an active T cellmediated immune response is unnecessary. Therefore, modalities which induce humoral (B cell) immune responses have become favorable or desirable for AD vaccines [21][22][23][24][25].…”