Alzheimer’s disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The ‘amyloid cascade hypothesis’ posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aβ peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD. TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance. These results demonstrate progressive neurodegeneration of the Alzheimer type in these animals. The TgF344-AD rat fills a critical need for a next-generation animal model to enable basic and translational AD research.

Inflammation is a key pathological hallmark of Alzheimer's disease (AD), though its impact on disease progression and neurodegeneration remains an area of active investigation. Among numerous inflammatory cytokines associated with AD, interleukin-1β (IL-1β) in particular has been implicated in playing a pathogenic role. Here we sought to investigate whether inhibition of IL-1β signaling provides disease-modifying benefits in an AD mouse model, and if so, by what molecular mechanisms. We report that chronic dosing of 3xTg-AD mice with an IL-1 receptor (IL-1R) blocking antibody significantly alters brain inflammatory responses, alleviates cognitive deficits, markedly attenuates tau pathology, and partly reduces certain fibrillar and oligomeric forms of amyloid-β (Aβ). Alterations in inflammatory responses correspond to reduced NF-κB activity. Furthermore, inhibition of IL-1 signaling reduces the activity of several tau kinases in the brain, including cdk5/p25, GSK-3β and p38-MAPK, and also reduces phospho-tau levels. We also detected a reduction in the astrocyte-derived cytokine, S100B, and in the extent of neuronal Wnt/β-catenin signaling in 3xTg-AD brains, and provided in vitro evidence that these changes may, in part, provide a mechanistic link between IL-1 signaling and GSK-3β activation. Taken together, our results suggest that the IL-1 signaling cascade may be involved in one of the key disease mechanisms for AD.

The role of adjuvant on the T(h)1 and T(h)2 immune responses to Abeta-immunotherapy (Abeta(42 )peptide) was examined in wild-type mice. Fine epitope analysis with overlapping oligomers of the Abeta(42) sequence identified the 1-15 region as a dominant B cell epitope. The 6-20 peptide was recognized only weakly by antisera from mice administrated with Abeta(42) peptide formulated in complete Freund's adjuvant (CFA), alum or TiterMax Gold (TMG). However, mice immunized with Abeta(42) mixed with QS21 induced a significant antibody response to the 6-20 peptide. The only T cell epitope found was within the 6-28 sequence of Abeta(42). QS21 and CFA induced the strongest humoral response to Abeta, alum was intermediate, and TMG the weakest adjuvant. Analysis of antibody isotypes specific for Abeta indicates that alum induces primarily T(h)2-type immune response, whereas TMG, CFA and QS21 shift the immune responses toward a T(h)1 phenotype. Stimulation of splenocytes from Abeta-immunized mice with Abeta(40) peptide induced strikingly different cytokine expression profiles. QS21 and CFA induced significant IFN-gamma, IL-4 and tumor necrosis factor-alpha expression, whereas alum induced primarily IL-4 production. As T(h)1-type immune responses have been implicated in many autoimmune disorders, whereas T(h)2-type responses have been shown to inhibit autoimmune disease, the choice of adjuvant may be critical for the design of a safe and effective immunotherapy for Alzheimer's disease.

Increasing evidence points to soluble assemblies of aggregating proteins as a major mediator of neuronal and synaptic dysfunction. In Alzheimer disease (AD), soluble amyloid-␤ (A␤) appears to be a key factor in inducing synaptic and cognitive abnormalities. Here we report the novel finding that soluble tau also plays a role in the cognitive decline in the presence of concomitant A␤ pathology. We describe improved cognitive function following a reduction in both soluble A␤ and tau levels after active or passive immunization in advanced aged 3xTg-AD mice that contain both amyloid plaques and neurofibrillary tangles (NFTs). Notably, reducing soluble A␤ alone did not improve the cognitive phenotype in mice with plaques and NFTs. Our results show that A␤ immunotherapy reduces soluble tau and ameliorates behavioral deficit in old transgenic mice. Alzheimer disease (AD)2 is clinically marked by a progressive deterioration of memory and other cognitive functions. Two obligate neuropathological lesions occur in the AD brain: amyloid plaques, mainly formed by a small peptide called amyloid-␤ (A␤), and neurofibrillary tangles (NFTs) formed by the hyperphosphorylated microtubule-binding protein tau (1). The accumulation of A␤ plays a central role in the progression of the disease, and over the past several years, there has been a growing appreciation for the pathogenic effects of soluble assemblies of A␤, which may be the predominant toxic species for neurons (2-4). The causes underlying AD-related memory loss and other cognitive changes are likely to be multifactorial, and although evidence suggests that soluble A␤ is an excellent candidate to be the initial trigger (4), other elements of AD neuropathology almost certainly contribute to the progressive deterioration in the cognitive faculties. In this regard, it is likely that the manifestation of tau pathology plays a pivotal role that further exacerbates the cognitive decline in the presence of A␤ and other AD-related alterations. Pathological assemblies of tau can induce neurodegeneration and dementia in the absence of A␤, as occurs in disorders such as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP17) (5). Elucidating the relationship between these two proteins (A␤ and tau) and their synergistic effects on cognition is facilitated by the utilization of a transgenic model that develops both A␤ and tau pathology.The 3xTg-AD mice develop an age-dependent decline in the cognitive phenotype in both spatial and contextual learning and memory paradigms. The occurrence of intraneuronal A␤ appears to be a trigger for the onset of deficits in water maze spatial memory, an effect that is fully reversible by A␤ immunotherapy (6). However, as the mice age and extracellular A␤ and neurofibrillary pathology manifest, the mice show further cognitive decline, 3 although the role that plaques and tangles play on the deterioration of the cognitive phenotype is still unresolved. Postmortem evaluation of AD brains has provided some correlational evidence linking th...

Immunization of amyloid precursor protein transgenic mice with fibrillar β-amyloid (Aβ) prevents Alzheimer’s disease (AD)-like neuropathology. The first immunotherapy clinical trial used fibrillar Aβ, containing the B and T cell self epitopes of Aβ, as the immunogen formulated with QS21 as the adjuvant in the vaccine. Unfortunately, the clinical trial was halted during the phase II stage when 6% of the participants developed meningoencephalitis. The cause of the meningoencephalitis in the patients that received the vaccine has not been definitively determined; however, analysis of two case reports from the AN-1792 vaccine trial suggest that the meningoencephalitis may have been caused by a T cell-mediated autoimmune response, whereas production of anti-Aβ Abs may have been therapeutic to the AD patients. Therefore, to reduce the risk of an adverse T cell-mediated immune response to Aβ immunotherapy we have designed a prototype epitope vaccine that contains the immunodominant B cell epitope of Aβ in tandem with the synthetic universal Th cell pan HLA DR epitope, pan HLA DR-binding peptide (PADRE). Importantly, the PADRE-Aβ1–15 sequence lacks the T cell epitope of Aβ. Immunization of BALB/c mice with the PADRE-Aβ1–15 epitope vaccine produced high titers of anti-Aβ Abs. Splenocytes from immunized mice showed robust T cell stimulation in response to peptides containing PADRE. However, splenocytes from immunized mice were not reactivated by the Aβ peptide. New preclinical trials in amyloid precursor protein transgenic mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse events that occurred in the first clinical trial.