Olfactory epithelium amyloid‐β and paired helical filament‐tau pathology in Alzheimer disease

Arnold, Steven E.; Lee, Edward B.; Moberg, Paul J.; Stutzbach, Lauren; Kazi, Hala; Han, Liying; Lee, Virginia M.‐Y.; Trojanowski, John Q.

doi:10.1002/ana.21910

Cited by 183 publications

(133 citation statements)

References 66 publications

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“…Finally, an MRI study demonstrated that pronounced olfactory bulb and fiber tract atrophy, a specific hallmark of AD (Mundinano et al, 2011), is present already very early in MCI patients (Thomann et al, 2009). Along the same line, it was shown that dystrophic neurites in the olfactory epithelium show high accumulations of paired helical filaments (PHFs; precursor elements of neurofibrillary tangles) and intracellular APP/Aβ in AD patients (Arnold et al, 2010). However, a time-course of these changes still needs to be determined.…”

Section: Olfactory-limbic Pathways and Admentioning

confidence: 99%

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

et al. 2013

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Alzheimer's disease (AD) is one of the largest unmet medical concerns of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles, the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiological characteristic of late-onset AD. AbstractAlzheimer`s disease (AD) is one of the largest unmet medical needs of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles (NFTs), the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiology characteristic of late-onset AD.3

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Section: Olfactory-limbic Pathways and Admentioning

confidence: 99%

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

et al. 2013

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“…Olfactory dysfunction occurs early in AD (Talamo et al, 1989;Bacon et al, 1998;Hawkes, 2003;Doty, 2009;Arnold et al, 2010) and the olfactory connections are well-defined to enable a clear evaluation of neural circuitry. In mammals, axons from olfactory sensory neurons (OSNs) expressing the same odorant receptor converge to stereotyped positions in the olfactory bulb (OB) forming glomeruli, which are organized into a precise anatomical map of odorant receptor identity, the glomerular map (Axel, 1995;Mombaerts, 2006;Cummings and Belluscio, 2008).…”

Section: Introductionmentioning

confidence: 99%

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

Cheng

Bai

Steuer

et al. 2013

Journal of Neuroscience

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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.

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“…4). These features may account for the noticeable differences between the regional distribution patterns and progression of both pathologies: Although abnormal tau remains virtually confined to the CNS in AD (Arnold et al 2010;Braak and Del Tredici 2015a), synucleinopathy in PD develops in all divisions of the nervous system (CNS, ENS, and PNS) (Beach et al 2010;Del Tredici et al 2010;Del Tredici and Braak 2012; Malek et al 2014).Intracerebrally, the PD-associated process consistently begins (PD stage 1) in the OB (chiefly in the anterior olfactory nucleus) and/ or in the dmX (Fig. 4, dark purple) (Pearce et al 1995;Hawkes et al 1999;Del Tredici et al 2002;Braak et al 2003a;Bloch et al 2006;Fujishiro et al 2008;Beach et al 2009;Braak and Del Tredici 2009;Markesbery et al 2009).…”

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confidence: 99%

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

Braak

Tredici

2016

Cold Spring Harb Perspect Biol

108

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Experimental data indicate that transneuronal propagation of abnormal protein aggregates in neurodegenerative proteinopathies, such as sporadic Alzheimer's disease (AD) and Parkinson's disease (PD), is capable of a self-propagating process that leads to a progression of neurodegeneration and accumulation of prion-like particles. The mechanisms by which misfolded tau and a-synuclein possibly spread from one involved nerve cell to the next in the neuronal chain to induce abnormal aggregation are still unknown. Based on findings from studies of human autopsy cases, we review potential pathways and mechanisms related to axonal and transneuronal dissemination of tau (sporadic AD) and a-synuclein (sporadic PD) aggregates between anatomically interconnected regions. S poradic Alzheimer's disease (AD) and Parkinson's disease (PD) are human neurodegenerative disorders that do not occur in other vertebrate species. Pathological hallmark lesions in AD and PD involve only a few types of nerve cells, mainly projection neurons. These lesions develop at predetermined predilection sites and progress according to predictable patterns (Braak and Del Tredici 2009, 2015). In AD, disease-related lesions remain confined to the central nervous system (CNS), whereas in PD they develop not only in the CNS but also in the enteric (ENS) and peripheral (PNS) nervous systems. Both diseases are caused by misfolding of specific proteins that are associated with aberrant aggregation. AD is primarily characterized by pathological forms of the intraneuronal protein tau (Goedert et al. 2006;Iqbal et al. 2009) and, thereafter gradually, by extracellular deposits of the b-amyloid protein (Ab) (Alafuzoff et al. 2009;Haass et al. 2012;Masters and Selkoe 2012). In mature nerve cells, the highest concentrations of the protein tau usually are found in the axon. Key lesions in sporadic PD consist of aggregated forms of a-synuclein, a protein located chiefly in axons and their presynaptic terminals (Eisenberg and Jucker 2012;Jucker and Walker 2013;Kaufman and Diamond 2013;Goedert et al. 2014). Notably, all brain regions and all types of nerve cells consecutively involved in AD or PD are anatomically interconnected over considerable distances, thereby indicating that physical contact among such interconnected nerve cells plays a key role in the pathogenesis of both illnesses (Pearson et al. 1985;Saper et al. 1987;Pearson and Powell 1989;Pearson 1996;Duyckaerts et al. 1997;Braak and Del Tredici 2011b). Ab is deposited extracellularly and thus is not known to transfer from one nerve cell to the next in the neuronal chain (Fiala 2007;Kaufman and Diamond 2013).Here, we focus on potential pathways and mechanisms related to the postulated transmission and transneuronal dissemination of tau and a-synuclein between involved neurons and as yet uninvolved neurons in anatomically connected regions (Brundin et al. 2008Clavaguera et al. 2009Clavaguera et al. , 2013aDesplats et al. 2009;Luk et al. 2009;Angot et al. 2010 Angot et al. , 2012Frost and Diamond 2010;Goedert...

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Olfactory epithelium amyloid‐β and paired helical filament‐tau pathology in Alzheimer disease

Abstract: These data demonstrate that AD pathology in the OE is present in the majority of cases with pathologically verified AD and correlates with brain pathology. Future work may assess the utility of amyloid-beta and PHFtau measurement in OE as a biomarker for AD.

Cited by 183 publications

References 66 publications

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

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

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

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