Olfactory Functions Scale with Circuit Restoration in a Rapidly Reversible Alzheimer's Disease Model

Abstract

Neural circuits maintain a precise organization that is vital for normal brain functions and behaviors, but become disrupted during neurological disease. Understanding the connection between wiring accuracy and function to measure disease progression or recovery has been difficult because of the complexity of behavioral circuits. The olfactory system maintains well-defined neural connections that regenerate throughout life. We previously established a reversible in vivo model of Alzheimer's disease by overexpressing a humanized mutated amyloid precursor protein (hAPP) in olfactory sensory neurons (OSNs). Using this model, we currently show that hAPP is present in the OSN axons of mutant mice, which exhibit strong caspase3 signal and reduced synaptic protein expression by 3 weeks of age. In the olfactory bulb, we show that glomerular structure is distorted and OSN axonal convergence is lost. In vivo functional imaging experiments further demonstrate disruption of the glomerular circuitry, and behavioral assays reveal that olfactory function is significantly impaired. Because OSNs regenerate, we also tested if the system could recover from hAPP-induced disruption. We found that after 1 or 3 weeks of shutting-off hAPP expression, the glomerular circuit was partially restored both anatomically and functionally, with behavioral deficits similarly reversed. Interestingly, the degree of functional recovery tracked directly with circuit restoration. Together, these data demonstrate that hAPP-induced circuit disruption and subsequent recovery can occur rapidly and that behavior can provide a measure of circuit organization. Thus, olfaction may serve as a useful biomarker to both follow disease progression and gauge potential recovery.

Early hyperactivity in lateral entorhinal cortex is associated with elevated levels of AβPP metabolites in the Tg2576 mouse model of Alzheimer's disease

“…This hyper-excitability emerged by at least 3 MO and remained through at least 16 MO. These findings mirror other studies that have demonstrated the effect of AβPP metabolites in inducing neurotoxic effects (Bach, et al, 2001, Bertrand, et al, 2001, Cheng, et al, 2013, Cheng, et al, 2011, Devi and Ohno, 2012, Dewachter, et al, 2002, Lu, et al, 2000, McPhie, et al, 2001, Sopher, et al, 1994, Yankner, et al, 1989). However, to the best of our knowledge, this is the first investigation of this disrupted firing activity in the LEC in response to odor stimuli.…”

“…Cleavage by the latter results in a β C-terminal fragment (βCTF) that contains the Aβ domain and generates Aβ and AβPP intracellular cytoplasmic domain when further processed by γ-secretase (Zheng and Koo, 2006, Zheng and Koo, 2011). The human AβPP metabolites Aβ and AβPP-CTF have been shown to exhibit some level of cytotoxicity in the pre-depositing brain, ranging from inducing endosome anomalies and apoptosis (Bertrand, et al, 2001, Cheng, et al, 2013, Deyts, et al, 2012, Jiang, et al, 2010, Kayed, et al, 2003, Lauritzen, et al, 2012, Lu, et al, 2000, McPhie, et al, 2001, Nhan, et al, 2014, Tamayev and D’Adamio, 2012, Tamayev, et al, 2012, Upadhaya, et al, 2012) to causing abnormal rewiring of neurons (Cheng, et al, 2011) and functional disruption of synapses (Lacor, et al, 2004). …”

Protective Effects of Melatonin and Selenium against Apoptosis of Olfactory Sensory Neurons: A Rat Model Study

“…21 Caspase-3 is the predominant effector Caspase in mammalian tissues and caspase-3 activation induces caspase-3-activated DNase activity. This process causes apoptosis, karyorrhexis, shrinkage, and degradation of DNA.…”

The Role of Olfactory Challenge Tests in Incipient Dementia and Clinical Trial Design

“…From a broader perspective, the study of olfaction sits at the intersection of many vibrant disciplines, including neuroscience, genetics, and immunology [77,78]. For the AD field, animal model studies, some employing highly innovative techniques [79], are yielding important insights; neurogenesis within the olfactory structures holds treatment potential [80]; the possibility that biopsy of olfactory mucosa might aid early diagnosis is again under discussion [2•, 34]. As a window on the brain and disease, the olfactory system richly rewards study.…”