Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo

Cao, Liqun; Schrank, Benjamin R.; Rodriguez, Steven; Benz, Eric G.; Moulia, Thomas W.; Rickenbacher, Gregory T.; Gomez, Alexis C.; Levites, Yona; Edwards, Sarah R.; Golde, Todd E.; Hyman, Bradley T.; Barnea, Gilad; Albers, Mark W.

doi:10.1038/ncomms2013

Cited by 72 publications

(84 citation statements)

References 49 publications

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“…Progressive neuronal loss in the olfactory complex of NPC1 mice is likely responsible for the deficit because we observed significant reductions in the pool of OSNs in NPC1 mice, as previously described [22]. Interestingly, the over-expression of the amyloid precursor protein (APP) accelerates the synthesis of soluble Aβ and leads to aberrant axonal targeting and elimination of OSNs [27,28]. Considering that impaired lipid metabolism in NPC1 causes an abnormal processing of APP and Aβ accumulation [29], it is possible that OSN loss is induced by APP-and Aβ-mediated cytotoxicity in NPC1 mice.…”

Section: Discussionsupporting

confidence: 65%

Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann–Pick disease type C1 mice

Seo

Kim

Shin

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Progressive olfactory impairment is one of the earliest markers of neurodegeneration. However, the underlying mechanism for this dysfunction remains unclear. The present study investigated the possible role of microgliosis in olfactory deficits using a mouse model of Niemann-Pick disease type C1 (NPC1), which is an incurable neurodegenerative disorder with disrupted lipid trafficking. At 7weeks of age, NPC1 mutants showed a distinct olfactory impairment in an olfactory test compared with age-matched wild-type controls (WT). The marked loss of olfactory sensory neurons within the NPC1 affected olfactory bulb (NPC1-OB) suggests that NPC1 dysfunction impairs olfactory structure. Furthermore, the pool of neuroblasts in the OB was diminished in NPC1 mice despite the intact proliferative capacity of neural stem/progenitor cells in the subventricular zone. Instead, pro-inflammatory proliferating microglia accumulated extensively in the NPC1-OB as the disease progressed. To evaluate the impact of abnormal microglial activation on olfaction in NPC1 mice, a microglial inhibition study was performed using the anti-inflammatory agent Cyclosporin A (CsA). Importantly, long-term CsA treatment in NPC1 mice reduced reactive microgliosis, restored the survival of newly generated neurons in the OB and improved overall performance on the olfactory test. Therefore, our study highlights the possible role of microglia in the regulation of neuronal turnover in the OB and provides insight into the possible therapeutic applications of microglial inhibition in the attenuation or reversal of olfactory impairment.

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Section: Discussionsupporting

confidence: 65%

Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann–Pick disease type C1 mice

Seo

Kim

Shin

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In addition, even at pre-depositing ages, these changes may already be present (Cao, et al, 2012, Guerin, et al, 2009). In order to investigate this phenomenon, a total of 58 single-units for Tg2576 mice (n=19 3 MO, n=21 6 MO, n=18 16 MO) and 70 units for WT mice (n=23 3 MO, n=26 6 MO, n=21 16 MO) were recorded in LEC (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Fitzgerald

Nixon

et al. 2015

Experimental Neurology

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Alzheimer’s disease (AD) is a neurodegenerative disorder that is the most common cause of dementia in the elderly today. One of the earliest symptoms of AD is olfactory dysfunction. The present study investigated the effects of amyloid β precursor protein (AβPP) metabolites, including amyloid-β (Aβ) and AβPP C-terminal fragments (CTF), on olfactory processing in the lateral entorhinal cortex (LEC) using the Tg2576 mouse model of human AβPP over-expression. The entorhinal cortex is an early target of AD related neuropathology, and the LEC plays an important role in fine odor discrimination and memory. Cohorts of transgenic and age-matched wild-type (WT) mice at 3, 6, and 16 months of age (MO) were anesthetized and acute, single-unit electrophysiology was performed in the LEC. Results showed that Tg2576 exhibited early LEC hyperactivity at 3 and 6 MO compared to WT mice in both local field potential and single-unit spontaneous activity. However, LEC single-unit odor responses and odor receptive fields showed no detectable difference compared to WT at any age. Finally, the very early emergence of olfactory system hyper-excitability corresponded not to detectable Aβ deposition in the olfactory system, but rather to high levels of intracellular AβPP-CTF and soluble Aβ in the anterior piriform cortex (aPCX), a major afferent input to the LEC, by 3 MO. The present results add to the growing evidence of AβPP-related hyper-excitability, and further implicate both soluble Aβ and non-Aβ AβPP metabolites in its early emergence.

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“…Aβ has been implicated in developmental synaptic plasticity both in visual deprivation paradigms and in the development of the olfactory bulb (Cao et al, 2012; Kim et al, 2013). Moreover, in non-demented human subjects, oligomeric Aβ at a subset of synapses is associated with smaller synapse volume (Koffie et al, 2012), indicating that Aβ may play a role in synaptic plasticity.…”

Section: Role Of Tau and Aβ In Normal Synaptic Biologymentioning

confidence: 99%

The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

Spires‐Jones

Hyman

2014

Neuron

956

745

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Summary The collapse of neural networks important for memory and cognition, including death of neurons and degeneration of synapses, causes the debilitating dementia associated with Alzheimer’s disease (AD). We suggest that synaptic changes are central to the disease process. Amyloid beta and tau form fibrillar lesions that are the classical hallmarks of AD. Recent data indicate that both molecules may have normal roles at the synapse, and that the accumulation of soluble toxic forms of the proteins at the synapse may be on the critical path to neurodegeneration. Further, the march of neurofibrillary tangles through brain circuits appears to take advantage of recently described mechanisms of trans-synaptic spread of pathological forms of tau. These two key phenomena, synapse loss and the spread of pathology through the brain via synapses, make it critical to understand the physiological and pathological roles of amyloid beta and tau at the synapse.

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Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo

Cited by 72 publications

References 49 publications

Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann–Pick disease type C1 mice

Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann–Pick disease type C1 mice

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

The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

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