Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, UNAM-Campus Juriquilla, México.
J Alzheimers Dis. 2021;82(s1):S19-S35. doi: 10.3233/JAD-201392.
Deficits in odor detection and discrimination are premature symptoms of Alzheimer's disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-β peptide (Aβ), which can be prevented by reducing Aβ levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aβ accumulation and Aβ-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility needs further exploration.
To characterize the effects of Aβ on OB and PCx excitability/coupling and on olfaction.
Aβ oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in slices. Olfaction was assessed through the habituation/dishabituation test.
Aβ did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo. Moreover, the coherence between PCx-OB activities was also reduced by Aβ. Finally, Aβ treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in slices.
Our results show that Aβ-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD.
嗅觉察觉和辨别能力的缺陷是阿尔茨海默病（AD）的早期症状，与嗅球（OB）和梨状皮层（PCx）的病理标志相关。在过度产生淀粉样β肽（Aβ）的 AD 转基因小鼠中也出现了类似的嗅觉功能障碍，通过免疫和药理学手段降低 Aβ 水平可以预防这种障碍，这表明嗅觉功能障碍取决于 Aβ 的积累以及 Aβ 对 OB 和/或 PCx 的改变，以及它们的激活。然而，这种可能性需要进一步探索。
描述 Aβ 对 OB 和 PCx 兴奋性/偶联以及嗅觉的影响。
在评估 OB 和 PCx 的兴奋性和同步性之前两周，通过活体和脑片的场记录，将 Aβ 寡聚物溶液（包含寡聚物、单体和原纤维）或其载体脑室内注射。还在脑片中评估了 OB 到 PCx 的突触传递。通过习惯化/去习惯化测试评估嗅觉。
Aβ 不影响侧向嗅觉束向 PCx 的传递，但会降低气味习惯化和交叉习惯化。这种嗅觉功能障碍与体内 PCx 和 OB 网络活动功率的降低有关。此外，Aβ 还降低了 PCx-OB 活动之间的相干性。最后，Aβ 处理加剧了 4-氨基吡啶在切片中对 PCx 的兴奋作用。
我们的结果表明，Aβ 诱导的嗅觉功能障碍涉及嗅觉通路不同水平的一系列复杂病理变化，包括 PCx 兴奋性及其与 OB 的偶联改变。这些病理变化可能导致 AD 患者的嗅觉减退。
