Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology

Abstract

Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing ␤-amyloid peptide (A␤) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the A␤ peptide. Similar protection could be achieved by passive administration of some but not all monoclonal antibodies against A␤. In the current studies we sought to define the optimal antibody response for reducing neuropathology. Immune sera with reactivity against different A␤ epitopes and monoclonal antibodies with different isotypes were examined for efficacy both ex vivo and in vivo. The studies showed that: (i) of the purified or elicited antibodies tested, only antibodies against the N-terminal regions of A␤ were able to invoke plaque clearance; (ii) plaque binding correlated with a clearance response and neuronal protection, whereas the ability of antibodies to capture soluble A␤ was not necessarily correlated with efficacy; (iii) the isotype of the antibody dramatically influenced the degree of plaque clearance and neuronal protection; (iv) high affinity of the antibody for Fc receptors on microglial cells seemed more important than high affinity for A␤ itself; and (v) complement activation was not required for plaque clearance. These results indicate that antibody Fc-mediated plaque clearance is a highly efficient and effective process for protection against neuropathology in an animal model of Alzheimer's disease.I mmunization of the transgenic PDAPP mice with ␤-amyloid peptide (A␤)-derived immunogens results in an antibody response that facilitates the clearance of plaques within the central nervous system (CNS) (1-4). Although a number of mechanisms are likely to operate in this clearance response (5, 6), our previous findings strongly indicate that antibodymediated, Fc-dependent phagocytosis by microglial cells and͞or macrophages is important to the process (7). Importantly, a T cell response was not required for amyloid plaque clearance. When peripherally administered, antibodies against A␤ entered the CNS of PDAPP transgenic mice, decorated amyloid plaques, and induced plaque clearance. Comparing different antibodies in an ex vivo assay with sections of PDAPP or Alzheimer's disease (AD) brain, there was a strong correlation between those that produced ex vivo efficacy and those that were efficacious in vivo. Fc receptors on microglial cells were found to be key for the clearance response in this assay. However, it has been reported that antibody efficacy can also be obtained in vivo by mechanisms that are independent of Fc interactions (8). Studies have indicated that an antibody directed against the midportion of A␤, which cannot recognize amyloid plaques, appears to bind to soluble A␤ and reduce plaque deposition (6). In addition, it has been reported recently that short-term...

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

“…Recent studies report the success of both active and passive vaccination approaches to slowing and/or reversing the aggregation process, and its pathological consequences, in mouse models of light chain amyloidosis [71], Alzheimer's disease [77,79,80,[86][87][88][89][90] and mammalian prion diseases [76,[91][92][93]. 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).…”

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

“…This AN-1792 clinical trial was halted due to the development of meningoencephalitis in a small proportion of the subjects [21][22][23][24][25][26], but follow up studies have demonstrated that strong anti-Aβ antibody responses specific to the linear Aβ [1][2][3][4][5][6][7][8] peptide [27] in some patients reduced AD pathology and diminished the cognitive decline associated with the disease [24,[27][28][29][30][31][32][33]. These data along with preclinical studies demonstrated that anti-Aβ antibodies directed to N-terminal region of Aβ 42 are effective in clearance of amyloid plaques [16,34,35]. On the contrary, the strong autoreactive Th1-type response specific to Aβ is thought to underlie the development of meningoencephalitis observed in the AN-1792 trial [30,31,33].…”

Camelid single-domain antibody fragments: Uses and prospects to investigate protein misfolding and aggregation, and to treat diseases associated with these phenomena

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