Alterations in Piriform and Bulbar Activity/Excitability/Coupling Upon Amyloid-β Administration in vivo Related to Olfactory Dysfunction

Abstract

Background: 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 (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 was not directly tested before. Objective: To characterize the effects of Aβ on OB and PCx excitability/coupling and on olfaction. Methods: 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 vitro. Olfaction was assessed through the habituation/dishabituation test. Results: 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 vitro. Conclusion: 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.

Deleterious and protective effects of epothilone-D alone and in the context of amyloid β- and tau-induced alterations

“…To model amyloid and P-tau pathologies we used ICV injection of Aβ and rTg4510 transgenic mice, respectively (Peña-Ortega, 2013Torres-Flores and Peña-Ortega, 2022;Xolalpa-Cueva et al, 2022). AD-like cognitive alterations induced by ICV administration of Aβ have been previously demonstrated by several groups (Haghani et al, 2012;Peña-Ortega, 2013Eslamizade et al, 2015), including ours (Peña-Ortega, 2013Martínez-García et al, 2021;Torres-Flores and Peña-Ortega, 2022). On the other hand, rTg4510 transgenic mice have been useful to analyze the pathophysiology of tauopathies (Ramsden et al, 2005;SantaCruz et al, 2005;Xolalpa-Cueva et al, 2022) and the interaction between Aβ and P-tau (Busche et al, 2019).…”

“…Once the skull was exposed, a hole was drilled with the following coordinates (from Bregma): −1 mm medio-lateral, −0.25 antero-posterior. A microinjector was gently introduced into the lateral ventricle (2.8 mm from the skull) and a total of 5 μL of either the Aβ oligomers solution (500 pmoles; Martínez-García et al, 2021) or its vehicle (F12 medium; Hernández-Soto et al, 2019) was injected at 0.5 μL/min with a Hamilton syringe. Martínez-García et al (2021) and Desbène et al (2012) have shown that this ICV dose of Aβ is enough to induce cognitive and neurophysiological alterations in mice (Desbène et al, 2012;Martínez-García et al, 2021).…”

“…A microinjector was gently introduced into the lateral ventricle (2.8 mm from the skull) and a total of 5 μL of either the Aβ oligomers solution (500 pmoles; Martínez-García et al, 2021) or its vehicle (F12 medium; Hernández-Soto et al, 2019) was injected at 0.5 μL/min with a Hamilton syringe. Martínez-García et al (2021) and Desbène et al (2012) have shown that this ICV dose of Aβ is enough to induce cognitive and neurophysiological alterations in mice (Desbène et al, 2012;Martínez-García et al, 2021). Intracerebral Aβ leads to its long-lasting non-fibrillar accumulation in the tissue (Alvarado-Martínez et al, 2013;Zussy et al, 2011Zussy et al, , 2013Sharma et al, 2016;Torres-Flores and Peña-Ortega, 2022).…”

Translational Research and Drug Discovery for Neurodegeneration: Challenges for Latin America

“…These observations are linked to concomitant changes in glutamate and GABA that affect the excitatory and inhibitory balance of retinal circuits. Martinez-García et al [3] also describe alterations in piriform cortical excitability that may contribute to olfactory dysfunction in AD.…”

Noradrenergic Modulation of the Piriform Cortex: A Possible Avenue for Understanding Pre-Clinical Alzheimer’s Disease Pathogenesis

“…In addition, both amyloid and tau generated animal models of AD exhibit neurodegeneration in olfactory regions and olfactory deficits (Cassano et al, 2011;Wesson et al, 2011;Saiz-Sanchez et al, 2012;Gandy et al, 2013;Kong et al, 2018;Adlimoghaddam et al, 2019;Ghosh et al, 2019). Several of these models point to PC specific dysfunction, due to increased expression of Aβ, tau and glycogen synthase kinase-3β in the PC compared to other odor sensory regions (Macknin et al, 2004;Cassano et al, 2011;Gandy et al, 2013), and direct disruption of PC function and PC-olfactory bulb (OB) coupling (Martinez-Garcia et al, 2021).…”