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Vaccination against amyloid ␤-peptide (A␤) has been shown to be successful in reducing A␤ burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although A␤ immunization did not show T cell infiltrates in the brain of these mice, an A␤ vaccination trial resulted in meningoencephalitis in 6% of patients with AD. Here, we explore the characteristics and specificity of A␤-induced, T cell-mediated encephalitis in a mouse model of the disease. We demonstrate that a strong A␤-specific T cell response is critically dependent on the immunizing T cell epitope and that epitopes differ depending on MHC genetic background. The amounts and the ratio between the two forms and their deposition in the brain are affected by mutations in the APP and presenilin genes or the presence of the ApoE4 allele (3, 4). Immunolabeling of extracellular A␤ in the brain reveals neuritic and diffuse plaques. The former are colocalized with activated microglia and astrocytes as well as degenerating neurons, whereas the latter do not clearly associate with glial activation or neurotoxicity (5). Recent findings also demonstrate a role for A␤ synaptotoxicity independent of plaques, possibly mediated by soluble A␤ oligomers at intra-and extracellular compartments (6-9).Parenteral immunization of APP transgenic (Tg) mice with synthetic A␤ in adjuvant can markedly decrease the number and density of A␤ deposits in the brain, with concomitant improvement in neuritic dystrophy and gliosis (10, 11). Positive effects have also been found after repetitive mucosal (intranasal) administration of the A␤ peptide to Tg mice (12, 13). Passive transfer of A␤ antibodies has shown similar beneficial neuropathological effects (14-16); however, brain hemorrhage appears as a possible side effect of this approach if tested in mice with cerebral amyloid angiopathy (7).The finding that active vaccination with A␤ had profound A␤-lowering effects in an animal model of AD led to a clinical trial in which an A␤1-42 synthetic peptide was administered parenterally with adjuvant to patients with mild to moderate AD. Although a phase I safety study in a small number of patients did not reveal significant side effects, a subsequent phase II trial was discontinued shortly after its initiation, when Ϸ6% of the treated patients developed meningoencephalitis (17). Nonetheless, a cohort of patients with AD vaccinated with A␤ have shown promising results, demonstrating slower decline of cognitive functions over a 1-year period, which was evident also in patients who experienced transient encephalitis (18). Postmortem analysis of brain sections revealed decreased A␤ plaques in neocortex regions associated with activated microglia and T cell infiltrates in the CNS, as compared with unimmunized patients with AD (19).The meningoencephalitis observed after A␤ vaccination of patients with AD is postulated to be the result of activation of A␤-reactive T cells in the periphery and their migration to A␤ plaques in the brain. Understanding the factors that are required to ...

Alzheimer disease (AD) is characterized by the progressive deposition of the 42-residue amyloid beta protein (Abeta) in brain regions serving memory and cognition. In animal models of AD, immunization with Abeta results in the clearance of Abeta deposits from the brain. However, a trial of vaccination with synthetic human Abeta1-42 in AD resulted in the development of meningoencephalitis in some patients. We measured cellular immune responses to Abeta in middle-aged and elderly healthy subjects and in patients with AD. A significantly higher proportion of healthy elderly subjects and patients with AD had strong Abeta-reactive T cell responses than occurred in middle-aged adults. The immunodominant Abeta epitopes in humans resided in amino acids 16-33. Epitope mapping enabled the identification of MHC/T cell receptor (TCR) contact residues. The occurrence of intrinsic T cell reactivity to the self-antigen Abeta in humans has implications for the design of Abeta vaccines, may itself be linked to AD susceptibility and course, and appears to be associated with the aging process.

Alzheimer's disease is a dementia that involves progressive deposition of amyloid ␤-protein (A␤) in brain regions important for memory and cognition, followed by secondary inflammation that contributes to the neuropathologic process. Immunization with A␤ can reduce cerebral A␤ burden and consequent neuropathologic changes in the brains of mice transgenic for the ␤-amyloid precursor protein (APP). We found that transgenic expression of human APP in B6SJL mice, under the prion promoter, results in immune hyporesponsiveness to human A␤, in terms of both antibody and cellular immune responses. The decreased antibody responses were related not to B cell tolerance but rather to the inability of A␤-specific T cells to provide help for antibody production. The immune hyporesponsiveness could be overcome if T cell help was provided by coupling an A␤ B cell epitope to BSA. Our results suggest that expression of APP in transgenic mice is associated with an A␤-specific impaired adaptive immune response that may contribute to the neuropathology. Moreover, humans with lifelong elevation of brain and peripheral A␤ (e.g., patients with presenilin mutations or Down syndrome) could have reduced immune responses to A␤ vaccination. A lzheimer's disease (AD) is a highly prevalent dementia that is associated with the abnormal accumulation and aggregation of amyloid ␤-peptide (A␤), a process that precedes neuronal injury (reviewed in ref. 1). Accumulating evidence suggests that aggregated forms of A␤ extracellularly, and perhaps also intracellularly, have neurotoxic properties (1-4). Moreover, the autosomal dominant familial forms of AD involve mutations in the genes encoding ␤-amyloid precursor protein (APP), presenilin 1 (PS1), or PS2, and these mutations all cause increased production and accumulation of A␤, a process that begins many years before clinical symptoms (1). A␤ is also overproduced in trisomy 21 (Down syndrome) patients, who overexpress APP from birth, thus making them more susceptible to AD (5, 6). Although there are numerous unresolved issues regarding the molecular and cellular cytotoxic events mediating AD, it is likely that A␤ plays a very early and central role in both the inherited and sporadic forms of the disease.The immune system also appears to participate in AD pathogenesis (7-11). Moreover, immune-based strategies have been shown to be effective in clearing A␤ from the brains of APP transgenic (Tg) mice (12-15). A␤ deposition causes activation of microglia and astrocytes at sites of its accumulation, followed by the induction of an inflammatory response (9,10,16). This inflammatory response may represent in part an attempt by the immune system to clear excess amounts of A␤. The proinflammatory environment in the brain may become chronic probably because of progressive accumulation of A␤ and its aggregation into forms that are less efficiently cleared and͞or more cytotoxic to neurons (7, 10). We hypothesized that chronic exposure of the immune system to A␤ in humans and mouse models might lead to hyporespons...