In Vivo Olfactory Model of APP-Induced Neurodegeneration Reveals a Reversible Cell-Autonomous Function

Developmental Neural Plasticity Unit, National Institute of Neurological Disorders and Stroke, and Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda Maryland 20892, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2011; 31(39):13699-704. DOI: 10.1523/JNEUROSCI.1714-11.2011
Source: PubMed


Amyloid precursor protein (APP) has long been linked to the neurodegeneration of Alzheimer's disease (AD), but the associated cell death has been difficult to capture in vivo, and the role of APP in effecting neuron loss is still unclear. Olfactory dysfunction is an early symptom of AD with amyloid pathology in the olfactory epithelium correlating well to the brain pathology of AD patients. As olfactory sensory neurons (OSNs) regenerate continuously with immature and mature OSNs coexisting in the same olfactory epithelium, we sought to use this unique system to study APP-induced neurodegeneration. Here we have developed an olfactory-based transgenic mouse model that overexpresses humanized APP containing familial AD mutations (hAPP) in either mature or immature OSNs, and found that despite the absence of extracellular plaques a striking number of apoptotic neurons were detected by 3 weeks of age. Importantly, apoptosis was restricted to the specific population overexpressing hAPP, either mature or immature OSNs, sparing those without hAPP. Interestingly, we observed that this widespread neurodegeneration could be rapidly rescued by reducing hAPP expression levels in immature neurons. Together, these data argue that overexpressing hAPP alone could induce cell-autonomous apoptosis in both mature and immature neurons, challenging the notion that amyloid plaques are necessary for neurodegeneration. Furthermore, we show that hAPP-induced neurodegeneration is reversible, suggesting that AD-related neural loss could potentially be rescued. Thus, we propose that this unique in vivo model will not only help determine the mechanisms underlying AD-related neurodegeneration but also serve as a platform to test possible treatments.

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    • "Overexpression of hAPP causes a large scale apoptosis of OSNs already by 3 weeks of age in which the glomerular layer and the olfactory nerve layer were shown to be much thinner, with a massive loss of glomeruli in the mutant mice compared to the control (Cheng et al., 2013). As OSNs project their axons directly to OB glomeruli, this is consistent with the loss of OSNs that was observed at the olfactory epithelium (Cheng et al., 2011). Here we show that this disruption in OSNs resulted also in a glomerular layer with a lower manganese enhancement and almost complete elimination of the olfactory nerve layer. "
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    ABSTRACT: Manganese Enhanced MRI (MEMRI) was used to detect specific laminar changes in the olfactory bulb (OB) to follow the progression of amyloid precursor protein (APP)-induced neuronal pathology and its recovery in a reversible olfactory based Alzheimer's disease (AD) mouse model. Olfactory dysfunction is an early symptom of AD, which suggests that olfactory sensory neurons (OSNs) may be more sensitive to AD related factors than neurons in other brain areas. Previously a transgenic mouse model was established that causes degeneration of OSNs by overexpressing humanized APP (hAPP), which results in a disruption of olfactory circuitry with changes in glomerular structure. In the present work, OB volume and manganese enhancement of the glomerular layer in OB were decreased in mutant mice. Turning off APP overexpression with doxycycline produced a significant increase in manganese enhancement of the glomerular layer after only 1 week, and further recovery after 3 weeks, while treatment with Aβ antibody produced modest improvement with MRI measurements. Thus, MEMRI enables a direct tracking of laminar specific neurodegeneration through a non-invasive in vivo measurement. The use of MRI will enable assessment of the ability of different pharmacological reagents to block olfactory neuronal loss and can serve as a unique in vivo screening tool to both identify potential therapeutics and test their efficacy. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 05/2015; 118. DOI:10.1016/j.neuroimage.2015.05.045 · 6.36 Impact Factor
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    • "Here, we show direct evidence that Aβ oligomers trigger a delayed loss of the ability to smell (Figure 4), which may be due to the actions of soluble and/or insoluble Aβ. Thus, our data support previous work showing that Aβ alters the activity of the OB network, resulting somewhat later in an inability to process olfactory information, as occurs in patients with AD and in transgenic animals [15,20,24]. Our demonstration of Aβ-induced OB dysfunction indicates that studies of the cellular mechanisms involved will help to understand AD pathology and reveal potential therapeutic targets against this disease. "
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    ABSTRACT: Early olfactory dysfunction has been consistently reported in both Alzheimer's disease (AD) and in transgenic mice that reproduce some features of this disease. In AD transgenic mice, alteration in olfaction has been associated with increased levels of soluble amyloid beta protein (Aβ) as well as with alterations in the oscillatory network activity recorded in the olfactory bulb (OB) and in the piriform cortex. However, since AD is a multifactorial disease and transgenic mice suffer a variety of adaptive changes, it is still unknown if soluble Aβ, by itself, is responsible for OB dysfunction both at electrophysiological and behavioral levels. Thus, here we tested whether or not Aβ directly affects OB network activity in vitro in slices obtained from mice and rats and if it affects olfactory ability in these rodents. Our results show that Aβ decreases, in a concentration- and time-dependent manner, the network activity of OB slices at clinically relevant concentrations (low nM) and in a reversible manner. Moreover, we found that intrabulbar injection of Aβ decreases the olfactory ability of rodents two weeks after application, an effect that is not related to alterations in motor performance or motivation to seek food and that correlates with the presence of Aβ deposits. Our results indicate that Aβ disrupts, at clinically relevant concentrations, the network activity of the OB in vitro and can trigger a disruption in olfaction. These findings open the possibility of exploring the cellular mechanisms involved in early pathological AD as an approach to reduce or halt its progress.
    PLoS ONE 09/2013; 8(9):e75745. DOI:10.1371/journal.pone.0075745 · 3.23 Impact Factor
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    • "Interestingly, a recently identified mutation adjacent to β-site (A673T) of APP gene was shown to result in Aβ reduction and protection against cognitive decline in the elderly without AD [22]. On the other hand, however, overexpression of FAD-linked mutant APP could lead to olfactory sensory neuron apoptosis in the absence of amyloid plaque, which might be the mechanism of deficits in odor detection, one of the earliest AD symptoms [23]. All these indicate that both APP genomic duplication and mutations can lead to changes in APP function and subsequent Aβ metabolism, strongly implicating a central role of not only APP but also its β-cleavage in pathogenesis of AD. "
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    ABSTRACT: Alzheimer's disease (AD) is a common neurodegenerative disease characterized clinically by progressive deterioration of memory, and pathologically by histopathological changes including extracellular deposits of amyloid-beta (A-beta) peptides forming senile plaques (SP) and the intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau in the brain. This review focused on the new developments of amyloid cascade hypothesis with details on the production, metabolism and clearance of A-beta, and the key roles of some important A-beta-related genes in the pathological processes of AD. The most recent research advances in genetics, neuropathology and pathogenesis of the disease were also discussed.
    Translational Neurodegeneration 09/2012; 1(1):18. DOI:10.1186/2047-9158-1-18
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