Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease

Abstract

Active immunization with the amyloid ␤ (A␤) peptide has been shown to decrease brain A␤ deposition in transgenic mouse models of Alzheimer's disease and certain peripherally administered anti-A␤ antibodies were shown to mimic this effect. In exploring factors that alter A␤ metabolism and clearance, we found that a monoclonal antibody (m266) directed against the central domain of A␤ was able to bind and completely sequester plasma A␤. Peripheral administration of m266 to PDAPP transgenic mice, in which A␤ is generated specifically within the central nervous system (CNS), results in a rapid 1,000-fold increase in plasma A␤, due, in part, to a change in A␤ equilibrium between the CNS and plasma. Although peripheral administration of m266 to PDAPP mice markedly reduces A␤ deposition, m266 did not bind to A␤ deposits in the brain. Thus, m266 appears to reduce brain A␤ burden by altering CNS and plasma A␤ clearance.A bundant evidence suggests that a key event in Alzheimer's disease (AD) pathogenesis is the conversion of the amyloid ␤ (A␤) peptide from soluble to aggregated forms in the brain. A␤, the principal proteinaceous component of plaque core and cerebrovascular amyloid, is composed of aggregates of the 4-kDa A␤ peptide (1). A␤ is predominantly 40-42 aa in length and is a normal, soluble proteolytic product of the amyloid precursor protein (APP), a large integral membrane protein expressed at high levels in the brain (2). Studies of mutations in APP and the presenilins, which cause early-onset, autosomal dominant, familial AD have revealed one common molecular consequence; they all increase A␤ production or increase the ratio of A␤ 42 ͞ A␤ 40 (3-6). Because A␤ 42 is more prone to aggregate, this appears to increase the probability that A␤ aggregation, amyloid deposition, and other downstream consequences will ensue, resulting in AD neuropathology.Production of A␤ via APP processing, however, is not the only factor that can influence the probability of A␤ deposition. Evidence has accumulated that indicates that factors regulating A␤ catabolism (7), clearance (8, 9), and aggregation (10) are also critical in regulating A␤ metabolism. For example, the 4 allele of apolipoprotein E (apoE) is a major AD risk factor, and apoE plays an important role in A␤ deposition (11). In vitro and in vivo studies indicate that apoE does not appear to play a role in A␤ production per se but influences A␤ clearance, aggregation, conformation, and toxicity (10-17). Other A␤ binding proteins may have similar or distinct effects (10). The transport of exogenous A␤ between the central nervous system (CNS) and plasma also may regulate brain A␤ levels (9). Recent studies have demonstrated that exogenous A␤ 40 is rapidly transported from cerebrospinal fluid (CSF) to plasma with an elimination half-life from brain of Յ30 min (8, 9). Because ''physiological'' A␤-binding proteins (e.g., apoJ͞apoE) can influence the transport͞flux of A␤ between CNS and͞or plasma (9, 18, 19), we became interested in whether exogenous A␤ binding molecules might b...

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

“…59 The second hypothesis did not rely on anti-Ab antibodies crossing the blood brain barrier. Rather, the "peripheral sink hypothesis" proposed by DeMattos et al [72][73][74] involved the sequestering of Ab in an immune complex in the blood, thereby lowering the level of free Ab, which contributed to a net efflux of Ab from the brain. They also suggested that therapeutically relevant concentrations of antiAb antibodies do not cross the blood brain barrier (BBB), as suggested by the theoretical calculations of the levels of both anti-Ab antibodies and Ab in the serum and CNS.…”

Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Aβ antibody response with Alum to Quil A adjuvant switch

“…Briefly, the N-terminus of the immunodominant B cell epitope of Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] was synthesized in tandem with a promiscuous foreign T cell epitope, PADRE (aK-Cha-VAAWTLKAAa, where "a" is D alanine and "Cha" is L-cyclohexylalanine) as Multiple Antigenic Peptides (MAP), which contain a core matrix of 4 branching lysines [42,43] to generate PADRE-Aβ 1-15 -MAP molecules (Invitrogen Inc., CA).…”

“…One potentially powerful strategy for reducing the level of Aβ in the brain is immunotherapy, in which antibodies specific to Aβ facilitate the clearance of amyloid deposits [10][11][12][13][14][15][16][17][18]. The first human AD vaccine consisted of fibrillar Aβ 42 formulated in QS21 adjuvant (AN-1792 trial) that induced strong Th1-type anti-Aβ immune responses [19], even in Th2-prone BALB/c mice [20].…”

“…In the present study, we compared the immunogenicity of our novel prototype epitope vaccine that contains the immunodominant B cell epitope of Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] in tandem with the synthetic universal helper T cell epitope, PADRE (PADRE-Aβ 1-15 -MAP) [36] formulated in Th1-type adjuvant (Quil A) or Th2-type adjuvant (Alum). To identify an acceptable adjuvant formulation for use in future pre-clinical and clinical trials, we tested the use of different combinations of Quil A and Alum in BALB/c and C57BL/6 mice of two different haplotypes H-2 d and H-2 b , respectively.…”

Impact of amyloid imaging on drug development in Alzheimer's disease

“…This finding was extended to the PDAPP strain of mice by Dodart and colleagues [50]. This group previously reported that chronic treatment of PDAPP mice with the m266 anti-Aβ antibody (every 2 weeks from 4 to 9 months of age) reduced Aβ burden at least in part by increasing peripheral clearance [55]. In the subsequent study in 24 month-old PDAPP mice [50], they found that a "subchronic" six-week course of m266 immunotherapy reversed the cognitive deficits measured, but did not decrease the Aβ immunohistochemical burden (brain Aβ levels were not determined by ELISA).…”