Immunization with Small Amyloid-ß-derived Cyclopeptide Conjugates Diminishes Amyloid-ß-Induced Neurodegeneration in Mice.

BACKGROUND: Soluble oligomeric (misfolded) species of amyloid-ß (Aß) are the main mediators of toxicity in Alzheimer's disease (AD). These oligomers subsequently form aggregates of insoluble fibrils that precipitate as extracellular and perivascular plaques in the brain. Active immunization against Aß is a promising disease modifying strategy. However, eliciting an immune response against Aß in general may interfere with its biological function and was shown to cause unwanted side-effects. Therefore, we have developed a novel experimental vaccine based on conformational neo-epitopes that are exposed in the misfolded oligomeric Aß, inducing a specific antibody response. OBJECTIVE: Here we investigate the protective effects of the experimental vaccine against oligomeric Aß1-42-induced neuronal fiber loss in vivo. METHODS: C57BL/6 mice were immunized or mock-immunized. Antibody responses were measured by enzyme-linked immunosorbent assay. Next, mice received a stereotactic injection of oligomeric Aß1-42 into the nucleus basalis of Meynert (NBM) on one side of the brain (lesion side), and scrambled Aß1-42 peptide in the contralateral NBM (control side). The densities of choline acetyltransferase-stained cholinergic fibers origination from the NBM were measured in the parietal neocortex postmortem. The percentage of fiber loss in the lesion side was determined relative to the control side of the brain. RESULTS: Immunized responders (79%) showed 23% less cholinergic fiber loss (p = 0.01) relative to mock-immunized mice. Moreover, fiber loss in immunized responders correlated negatively with the measured antibody responses (R2 = 0.29, p = 0.02). CONCLUSION: These results may provide a lead towards a (prophylactic) vaccine to prevent or at least attenuate (early onset) AD symptoms.

Time-place learning over a lifetime: absence of memory loss in trained old mice.

Time-place learning (TPL) offers the possibility to study the functional interaction between cognition and the circadian system with aging. With TPL, animals link biological significant events with the location and the time of day. This what-where-when type of memory provides animals with an experience-based daily schedule. Mice were tested for TPL five times throughout their lifespan and showed (re)learning from below chance level at the age of 4, 7, 12, and 18 mo. In contrast, at the age of 22 mo these mice showed preservation of TPL memory (absence of memory loss), together with deficiencies in the ability to update time-of-day information. Conversely, the majority of untrained (naïve) mice at 17 mo of age were unable to acquire TPL, indicating that training had delayed TPL deficiencies in the mice trained over lifespan. Two out of seven naïve mice, however, compensated for correct performance loss by adapting an alternative learning strategy that is independent of the age-deteriorating circadian system and presumably less cognitively demanding. Together, these data show the age-sensitivity of TPL, and the positive effects of repeated training over a lifetime. In addition, these data shed new light on aging-related loss of behavioral flexibility to update time-of-day information.