Chronic anti-murine Aβ immunization preserves odor guided behaviors in an Alzheimer's β-amyloidosis model

Abstract

Olfaction is often impaired in Alzheimer‟s disease (AD) and is also dysfunctional in mouse models of the disease. We recently demonstrated that short-term passive anti-murine-Aβ immunization can rescue olfactory behavior in the Tg2576 mouse model overexpressing a human mutation of the amyloid precursor protein (APP) after β-amyloid deposition. Here we tested the ability to preserve normal olfactory behaviors by means of long-term passive anti-murine-Aβ immunization. Seven-month-old Tg2576 and non-transgenic littermate (NTg) mice were IP-injected biweekly with the m3.2 murine-Aβ-specific antibody until 16 months of age when mice were tested in the odor habituation test. While Tg2576 mice treated with a control antibody showed elevations in odor investigation times and impaired odor habituation compared to NTg, olfactory behavior was preserved to NTg levels in m3.2-immunized Tg2576 mice. Immunized Tg2576 mice had significantly less β-amyloid immunolabeling in the olfactory bulb and entorhinal cortex, yet showed elevations in Thioflavin-S labeled plaques in the piriform cortex. No detectable changes in APP metabolite levels other than Aβ were found following m3.2 immunization. These results demonstrate efficacy of chronic, long-term anti-murine-Aβ m3.2 immunization in preserving normal odor-guided behaviors in a human APP Tg model. Further, these results provide mechanistic insights into olfactory dysfunction as a biomarker for AD by yielding evidence that focal reductions of Aβ may be sufficient to preserve olfaction.

Cortical Odor Processing in Health and Disease

“…Guerin et al (2009) using the often employed Tg2576 mouse found no apparent odor detection deficits but pronounced odor habituation changes at 7 months of age despite a lack of Aβ accumulation in any brain region. Our group using the same mouse model found similar results in odor habituation beginning at 6 months of age (Wesson et al, 2010, 2011, 2013). Preventing or reversing the Aβ accumulation restored normal odor habituation (Cramer et al, 2012; Morales-Corraliza et al, 2013; Wesson et al, 2011, 2013; Yang et al, 2011), while inducing damage to the locus coeruleus noradrenergic system exacerbated them (Rey et al, 2012).…”

“…Our group using the same mouse model found similar results in odor habituation beginning at 6 months of age (Wesson et al, 2010, 2011, 2013). Preventing or reversing the Aβ accumulation restored normal odor habituation (Cramer et al, 2012; Morales-Corraliza et al, 2013; Wesson et al, 2011, 2013; Yang et al, 2011), while inducing damage to the locus coeruleus noradrenergic system exacerbated them (Rey et al, 2012). Finally, in a test of hippocampal-dependent odor memory, Young et al (2009) found that as Tg2576 aged, they were able to remember fewer odors and made more errors in an odor span task designed to assess working memory for 12–22 odors.…”

Amyloid-β Deposition and Olfactory Dysfunction in an Alzheimer's Disease Model

“…Since PC encodes higher-order representations of odor quality, identity, and familiarity [41], and is associated with olfactory learning and memory, disrupting PC activity would impair corresponding olfactory functions [14]. Along with the facts that A␤-dependent olfactory dysfunction occurs in young Tg2576 mice [61] and normal odor-guided behaviors are preserved by long-term A␤ oligomer antibody treatment [62], our results suggest that soluble A␤ aggregates in olfactory cortices play an important role in early olfactory deficits.…”

Spared Piriform Cortical Single-Unit Odor Processing and Odor Discrimination in the Tg2576 Mouse Model of Alzheimer's Disease

“…This pathological olfactory circuit hyperactivity emerges by 6 months of age, which corresponds with deficits in olfactory habituation in early age groups [15], [20]. Furthermore, reducing soluble Aβ levels in a variety of ways restores olfactory cortical physiology and olfactory habituation [14], [20]–[22].…”