Passive immunization studies show similar efficacy in reducing brain A/amyloid and preserving memory in transgenic mouse models of AD [13,14], but the passive immunization approach is also limited by excessive neuroinflammation and vasogenic edema in a subset of treated individuals with AD

Passive immunization studies show similar efficacy in reducing brain A/amyloid and preserving memory in transgenic mouse models of AD [13,14], but the passive immunization approach is also limited by excessive neuroinflammation and vasogenic edema in a subset of treated individuals with AD. Passive immunization may reduce brain Fosdagrocorat A by at least two distinct mechanisms that are not mutually exclusive: 1) microglial phagocytosis of A/amyloid with increased cytokine production, which requires peripherally administered antibodies to cross the blood brain barrier [13], and 2) peripheral sequestration of A by antibody in the blood — referred to as the sink hypothesis [14]. revealed no change in brain A, decreased serum A, and increased CNS cytokine levels. Identical experiments in younger (17 month old) female 3 tg AD mice with intermediate AD-like neuropathologies revealed a trend towards decreased brain A and increased serum A accompanied by a decrease in CNS MCP-1. Conclusions These data suggest that passive immunization with PFA1 in 3 tg AD mice with intermediate disease burden, regardless of sex, is effective in mediating potentially therapeutic effects such as lowering brain A. In contrast, passive immunization of mice with a more advanced amyloid burden may result in potentially adverse effects (encephalitis and vasogenic edema) mediated by certain proinflammatory cytokines. Background A defining pathological hallmark of Alzheimer’s disease (AD) is the accumulation of A/amyloid deposits in brain. The generation and clearance of A, produced from amyloid precursor protein (APP) by – and -secretases, remain key therapeutic targets for transgenic AD mouse models and for Fosdagrocorat clinical studies [1]. A naturally exists as a monomer or as aggregates including oligomers, protofibrils, and fibrils. Of the two most Fosdagrocorat commonly generated isoforms of A, A40 and A42, the latter aggregates more readily to form amyloid fibrils [2,3]. Oligomers and protofibrils, the intermediate stages of A fibril formation, are neurotoxic in culture and in animal models [4-6] and these aggregates may correlate better with AD severity than neuritic plaque density [7,8]. Immunotherapy is an effective method of reducing brain A levels and preserving or improving behavioral outcome measures in transgenic mouse models of AD. Initial studies utilized an active immunization approach. Peripheral injections of synthetic human A prevented amyloid deposition, decreased CNS A/amyloid burden, and ameliorated memory deficits in mice [9-11]. However, when this therapy was translated to individuals with AD, the pivotal clinical trial was terminated early due to the development of excessive neuroinflammation (autoimmune encephalitis) in 6% of treated individuals [12]. Passive immunization with antibodies to A may offer a safer, and reversible, alternative by circumventing T-cell responses associated with neuroinflammation in active immunization protocols. Passive immunization studies show similar efficacy in reducing brain A/amyloid and preserving memory in transgenic mouse models of AD [13,14], but the passive immunization approach is also limited by excessive neuroinflammation and vasogenic edema in a subset of treated individuals with AD. Passive immunization may reduce brain A by at least two distinct mechanisms that are not mutually exclusive: 1) microglial phagocytosis of A/amyloid with increased cytokine production, which requires peripherally administered antibodies to cross the blood brain barrier [13], and 2) peripheral sequestration of A by antibody in the blood — referred to as the sink hypothesis [14]. The A antibody in the periphery may act as a Rabbit Polyclonal to Claudin 7 sink by binding A in the blood and promoting clearance of A from the brain to the periphery, resulting in increased plasma A following treatment. Others suggest, however, that peripherally-administered antibody also prolongs the half-life of A in blood, and this explains the resultant increase in plasma levels. To examine these possibilities, it is important to measure CNS cytokine levels in addition to serum and brain A levels following passive immunization. It is unknown whether immunotherapy may prove beneficial with high levels of CNS amyloid burden, or whether treatment may perhaps be limited to a subset of individuals in earlier disease stages. Alternatively, antibody dosage may be tailored to amyloid burden in order to minimize the risk of encephalitis and vasogenic edema. A recent clinical study reported increased vasogenic edema with higher antibody dosage and greater disease burden (as found in ApoE4-positive subjects) [15]. This is the first study to suggest differential responses to passive immunization perhaps due to.