Immunotherapies for various neurodegenerative diseases have recently emerged as a promising approach for clearing pathological protein conformers in these disorders. This type of treatment has not been assessed in models that develop neuronal tau aggregates as observed in frontotemporal dementia and Alzheimer's disease. Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. Females had more tau pathology than males but were also more receptive to the immunotherapy. The tau antibodies generated in these animals recognized pathological tau on brain sections. Performance on behavioral assays that require extensive motor coordination correlated with tau pathology in corresponding brain areas, and antibody levels against the immunogen correlated inversely with tau pathology. Interestingly, age-dependent autoantibodies that recognized recombinant tau protein but not the immunogen were detected in the P301L mice. To confirm that anti-tau antibodies could enter the brain and bind to pathological tau, FITC-tagged antibodies purified from a P301L mouse, with a high antibody titer against the immunogen, were injected into the carotid artery of P301L mice. These antibodies were subsequently detected within the brain and colocalized with PHF1 and MC1 antibodies that recognize pathological tau. Currently, no treatment is available for clearing tau aggregates. Our present findings may lead to a novel therapy targeting one of the major hallmarks of Alzheimer's disease and frontotemporal dementia.

Harnessing the immune system to clear protein aggregates is emerging as a promising approach to treat various neurodegenerative diseases. In Alzheimer's disease (AD), several clinical trials are ongoing using active and passive immunotherapy targeting the amyloid-␤ (A␤) peptide. Limited emphasis has been put into clearing tau/tangle pathology, another major hallmark of the disease. Recent findings from the first A␤ vaccination trial suggest that this approach has limited effect on tau pathology and that A␤ plaque clearance may not halt or slow the progression of dementia in individuals with mild-to-moderate AD. To assess within a reasonable timeframe whether targeting tau pathology with immunotherapy could prevent cognitive decline, we developed a new model with accelerated tangle development. It was generated by crossing available strains that express all six human tau isoforms and the M146L presenilin mutation. Here, we show that this unique approach completely prevents severe cognitive impairment in three different tests. This remarkable effect correlated well with extensive clearance of abnormal tau within the brain. Overall, our findings indicate that immunotherapy targeting pathological tau is very feasible for tauopathies, and should be assessed in clinical trials in the near future.

Immunization with amyloid-␤ (A␤) 1-42 has been shown to reduce amyloid burden and improve cognition in Alzheimer's disease (AD) model mice. In a human trial, possible cognitive benefit was found but in association with significant toxicity in a minority of patients. We proposed that immunization with nonfibrillogenic A␤ derivatives is much less likely to produce toxicity and have previously shown that one such derivative (K6A␤1-30) can reduce amyloid burden in mice to a similar extent as A␤1-42. Here, we immunized AD model mice (Tg2576) ]-vaccinated mice are likely to be related to peripheral clearance of A␤, because IgM does not cross the blood-brain barrier because of its large size. Our results indicate that these nontoxic A␤ derivatives produce an attenuated antibody response, which is less likely to be associated with negative side effects while having cognitive benefits.

The amyloid-␤ (A␤) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of A␤ peptide constitutes a critical event in the early disease pathogenesis. The direct binding between A␤ and apolipoprotein E (apoE) is an important factor implicated in both A␤ clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/A␤ interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed A␤12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length A␤. A␤12-28P binds with high affinity to apoE, preventing its binding to A␤, but has no direct effect on A␤ aggregation. A␤12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of A␤ plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of A␤ in two AD transgenic mice models. The treatment did not affect the levels of soluble A␤ fraction or A␤ oligomers, indicating that inhibition of the apoE/A␤ interaction in vivo has a net effect of increasing A␤ clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with A␤12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD.Alzheimer's pathology ͉ memory loss prevention ͉ peptide ͉ transgenic mice ͉ treatment A lzheimer's disease (AD) is the most common neurodegenerative disease worldwide, characterized by a progressive dysfunction in multiple cognitive domains and complex neuropathological features that include accumulation of amyloid-␤ (A␤) followed by synaptic dysfunction, formation of neurofibrillary tangles, and neuronal loss. With the expected increase in AD prevalence, as a function of the population aging, effective treatment for AD is critically needed. Multiple lines of evidence indicate that a disturbance of A␤ homeostasis is a paramount event in early disease pathogenesis (1). A␤ is a hydrophobic 39-to 43-aa peptide, which is derived from cleavage of a larger, synaptic transmembrane protein, the amyloid precursor protein (APP) (2). The accumulation of A␤ in the brain is determined by the rate of its generation versus in situ proteolytic degradation and clearance across the blood-brain-barrier [BBB; for review see Tanzi et al. (3)]. In the setting of increased concentration, A␤ monomers assemble into oligomers and fibrils and eventually become deposited, forming parenchymal plaques and cerebral amyloid angiopathy (CAA).Inheritance of the apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor identified so far. ApoE isotype inheritance modulates the prevalence, age of onset, and the burden of pathology in sporadic AD (4, 5). ApoE binds A␤ with high affinity a...

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Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-β (Aβ) 1-42, and the adjuvant, QS-21. To avoid this toxicity, we have been using Aβ derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque-and vascular-Aβ burden, Aβ levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Aβ deposit burden by 31% and Aβ levels by 30-37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Aβ burden or improve cognition. Significantly, the immunotherapy in the 11-24 months treatment group, that reduced Aβ burden, did not increase cerebral bleeding or vascular Aβ deposits in contrast to several Aβ antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Aβ burden when used with an adjuvant suitable for humans, without increasing vascular Aβ deposits or microhemorrhages.

Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to improve learning and memory in several preclinical models of Alzheimer’s disease (AD). Memantine has also been shown to reduce the levels of amyloid β (Aβ) peptides in human neuroblastoma cells as well as to inhibit Aβ oligomer-induced synaptic loss. In this study, we assessed whether NMDA receptor inhibition by memantine in transgenic mice expressing human amyloid-beta precursor protein (APP) and presenilin 1 (PS1) is associated with cognitive benefit and amyloid burden reduction by using object recognition, micromagnetic resonance imaging (µMRI), and histology. APP/PS1 Tg mice were treated either with memantine or with vehicle for a period of 4 months starting at 3 months of age. After treatment, the mice were subjected to an object recognition test and analyzed by ex vivo µMRI, and histological examination of amyloid burden. µMRI was performed following injection with gadolinium-DTPA-Aβ1–40. We found that memantine-treated Tg mice performed the same as wild-type control mice, whereas the performance of vehicle-treated Tg mice was significantly impaired (P = 0.0081, one-way ANOVA). Compared with vehicle-treated animals, memantine-treated Tg mice had a reduced plaque burden, as determined both histologically and by µMRI. This reduction in amyloid burden correlates with an improvement in cognitive performance. Thus, our findings provide further evidence of the potential role of NMDA receptor antagonists in ameliorating AD-related pathology. In addition, our study shows, for the first time, the utility of µMRI in conjunction with gadolinium-labeled Aβ labeling agents to monitor the therapeutic response to amyloid-reducing agents.