CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 8, Issue 1, 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]. The focus of this two volume series of reviews is on utilizing various types of immunotherapy to enhance clearance of the amyloid-beta (Aβ) peptide in the brain. The Aβ peptide has been targeted based on multiple lines of research, which have culminated in the amyloid hypothesis of AD, which assumes that the accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance [5]. The advent of anti-Aβ immunotherapy was initiated by the seminal report in Nature by Dale Schenk and his colleagues at Elan Pharmaceutical, where they showed that immunization of mice with the Aβ peptide prevented amyloid-plaque formation, neuritic dystrophy and astrogliosis, and that immunized older amyloid precursor protein (APP) transgenic (Tg) mice were able to clear preexisting forms of AD-like neuropathology [6]. Moreover, subsequent anti-Aβ immunization studies in APP/Tg mouse models of AD showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as non-transgenic mice [7, 8]. Additional studies using passive transfer of several monoclonal anti-Aβ antibodies identified antibodies as the principle therapeutic entity for clearance of CNS Aβ [9, 10]. However, the first immunotherapy clinical trial in AD patients, AN-1792, was halted when 6% of the Alzheimer's patients developed aseptic meningoencephalitis. Postmortem analysis of two cases with meningoencephalitis showed robust glial activation, T-cell infiltration and sporadic clearance of Aβ. Speculation on the cause(s) of the meningoencephalitis in patients that received the AN-1792 vaccine has focused on autoreactive anti-T Aβ and/or APP T cells and adjuvant-induced inflammation in the brain. The failure of the first clinical trial has encouraged the development of new approaches and alternative methods of immunotherapy for AD.

Immunotherapy has emerged as a leading new approach to the reduction of amyloid deposits in the brains of Alzheimer patients. At least 4 distinct actions of anti-Aβ antibodies have been proposed as contributing to the inhibition of amyloid deposition and its clearance. Critically, each of these proposed mechanisms may be acting simultaneously, and it is feasible that different antibodies may utilize each mechanism to a different extent. One of these proposed mechanisms involves the activation of microglia and the phagocytosis of Aβ peptide. In general this is assumed to proceed through the Fcγ-receptor binding by antibody opsonized Aβ aggregates, however modifying the microglial phenotype into one with a greater propensity for phagocytosing Aβ is also feasible, as microglia avidly phagocytose Aβ in vitro without antibody present. Evidence is presented supporting arguments that microglial activation does play a role in amyloid removal, particularly compacted amyloid deposits, under certain conditions. In addition to the specific antibody used, other considerations in comparing different reports of antibody action in APP mice include the age of the mice, the extent of pre-existing amyloid when therapy is initiated, the time point when the effects of the therapy are examined and the route of antibody administration. Future questions will consider the source of the activated microglia near the plaques after antibody administration (resident or peripheral) and the extent to which shifts in the microglial phenotype mediate some of the amyloid lowering actions of immunotherapy.

The main receptors for amyloid-beta peptide (Aβ) transport across the blood-brain barrier (BBB) from brain to blood and blood to brain are low-density lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE), respectively. In normal human plasma a soluble form of LRP1 (sLRP1) is a major endogenous brain Aβ ‘sinker’ that sequesters some 70 to 90 % of plasma Aβ peptides. In Alzheimer's disease (AD), the levels of sLRP1 and its capacity to bind Aβ are reduced which increases free Aβ fraction in plasma. This in turn may increase brain Aβ burden through decreased Aβ efflux and/or increased Aβ influx across the BBB. In Aβ immunotherapy, anti-Aβ antibody sequestration of plasma Aβ enhances the peripheral Aβ ‘sink action’. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Aβ antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Aβ antibody/ Aβ immune complexes are rapidly cleared from brain to blood via FcRn (neonatal Fc receptor) across the BBB. In a mouse model of AD, restoring plasma sLRP1 with recombinant LRP-IV cluster reduces brain Aβ burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Aβ is required for its direct interaction with sLRP and LRP-IV cluster which is completely blocked by the receptor-associated protein (RAP) that does not directly bind Aβ. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Aβ ‘sink’ action, hold potential to reduce brain Aβ and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.

There is substantial and compelling evidence that aggregation and accumulation of amyloid β protein (Aβ) plays a pivotal role in the development of Alzheimer's disease (AD); thus, numerous strategies to prevent Aβ aggregation and accumulation or to facilitate removal of preexisting deposits of Aβ are being evaluated as ways to treat or prevent AD [1, 2]. Pre-clinical studies in mice demonstrate the therapeutic potential of altering Aβ deposition by inducing a humoral immune response to fibrillar Aβ42 (fAβ42) or passively administering anti-Aβ antibodies (Abs) [3, 4], and both passive and active anti-Aβ immunotherapeutic approaches are now being tested in humans. Although a variety of mechanisms have been postulated regarding how Aβ immunotherapy might work to attenuate or in some circumstances clear Aβ from the brain, no mechanism has been definitively proven or disproven. Herein, we will review the various mechanisms that have been postulated. In addition we will discuss how a more thorough understanding of the pharmacokinetics of anti-Aβ Abs and their effects on Aβ levels and turnover provides insight into both the therapeutic potential and limitation of Aβ immunotherapy. We will conclude with a discussion of additional experimentation required to better understand the mechanism of action of anti-Aβ Abs in AD and optimize antibody (Ab) mediated therapy for AD.

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that results in severe cognitive decline. Amyloid plaques are a principal pathology found in AD and are composed of aggregated amyloid- beta (Aβ) peptides. According to the amyloid hypothesis, Aβ peptides initiate the other pathologies characteristic for AD including cognitive deficits. Immunotherapy against Aβ is a potential therapeutic for the treatment of humans with AD. While anti-Aβ immunotherapy has been shown to reduce amyloid burden in both mouse models and in humans, immunotherapy also exacerbates vascular pathologies. Cerebral amyloid angiopathy (CAA), that is, the accumulation of amyloid in the cerebrovasculature, is increased with immunotherapy in humans with AD and in mouse models of amyloid deposition. CAA persists in the brains of clinical trial patients that show removal of parenchymal amyloid. Mouse model studies also show that immunotherapy results in multiple small bleeds in the brain, termed microhemorrhages. The neurovascular unit is a term used to describe the cerebrovasculature and its associated cells-astrocytes, neurons, pericytes and microglia. CAA affects brain perfusion and there is now evidence that the neurovascular unit is affected in AD when CAA is present. Understanding the type of damage to the neurovascular unit caused by CAA in AD and the underlying cause of microhemorrhage after immunotherapy is essential to the success of therapeutic vaccines as a treatment for AD.

Individuals with early Alzheimer's disease (AD) suffer from a selective and profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by toxic Aβ oligomers (also known as ADDLs). ADDLs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. The AD-like cellular pathologies induced by ADDLs suggest their impact could provide a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Discovery of these new toxins has provided an appealing target for disease-modifying immunotherapy. For optimal protection against these toxins, antibodies should bind to the pathological oligomers without being depleted by their monomeric subunits, which are rapidly generated by membrane protein turnover. A solution to this problem is likely to come from the continued development of conformation-specific antibodies, as described here. Prototype conformation-specific antibodies, not yet in the clinic, have been introduced and utilized in multiple applications for their ability to bind with high specificity and affinity to ADDLs. It can be anticipated that further development of such antibodies for use in clinical trials will come in the near future.