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  • 1
    Online Resource
    Online Resource
    Bridging Molecular Genetics and Biomarkers in Lewy Body and Related Disorders
    Hindawi Limited ; 2011
    In:  International Journal of Alzheimer's Disease Vol. 2011 ( 2011), p. 1-18
    Details
    In: International Journal of Alzheimer's Disease, Hindawi Limited, Vol. 2011 ( 2011), p. 1-18
    Abstract: Recent advances have been made in defining the genetic and molecular basis of dementia with Lewy bodies (DLBs) and related neurodegenerative disorders such as Parkinson's disease (PD) and Parkinson's disease dementia (PDD) which comprise the spectrum of “Lewy body disorders” (LBDs). The genetic alterations and underlying disease mechanisms in the LBD overlap substantially, suggesting common disease mechanisms. As with the other neurodegenerative dementias, early diagnosis in LBD or even identification prior to symptom onset is key to developing effective therapeutic strategies, but this is dependent upon the development of robust, specific, and sensitive biomarkers as diagnostic tools and therapeutic endpoints. Recently identified mutations in the synucleins and other relevant genes in PD and DLB as well as related biomolecular pathways suggest candidate markers from biological fluids and imaging modalities that reflect the underlying disease mechanisms. In this context, several promising biomarkers for the LBD have already been identified and examined, while other intriguing possible candidates have recently emerged. Challenges remain in defining their correlation with pathological processes and their ability to detect DLB and related disorders, and perhaps a combined array of biomarkers may be needed to distinguish various LBDs.
    Type of Medium: Online Resource
    ISSN: 2090-0252
    URL: Article
    DOI: 10.4061/2011/842475
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2011
    detail.hit.zdb_id: 2573333-3
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  • 2
    Online Resource
    Online Resource
    ApoE4-Driven Accumulation of Intraneuronal Oligomerized A β 42 following Activation of the Amyloid Cascade In Vivo Is Mediated by a Gain of Function
    Hindawi Limited ; 2011
    In:  International Journal of Alzheimer's Disease Vol. 2011 ( 2011), p. 1-8
    Details
    In: International Journal of Alzheimer's Disease, Hindawi Limited, Vol. 2011 ( 2011), p. 1-8
    Abstract: Activating the amyloid cascade by inhibiting the A β -degrading enzyme neprilysin in targeted replacement mice, which express either apoE4 or apoE3, results in the specific accumulation of oligomerized A β 42 in hippocampal CA1 neurons of the apoE4 mice. We presently investigated the extent to which the apoE4-driven accumulation of A β 42 and the resulting mitochondrial pathology are due to either gain or loss of function. This revealed that inhibition of neprilysin for one week triggers the accumulation of A β 42 in hippocampal CA1 neurons of the apoE4 mice but not of either the corresponding apoE3 mice or apoE-deficient mice. At 10 days, A β 42 also accumulated in the CA1 neurons of the apoE-deficient mice but not in those of the apoE3 mice. Mitochondrial pathology, which in the apoE4 mice is an early pathological consequence following inhibition of neprilyisn, also occurs in the apoE-deficient but not in the apoE3 mice and the magnitude of this effect correlates with the levels of accumulated A β 42 and oligomerized A β 42 in these mice. These findings suggest that the rate-limiting step in the pathological effects of apoE4 on CA1 neurons is the accumulation of intracellular oligomerized A β 42 which is mediated via a gain of function property of apoE4.
    Type of Medium: Online Resource
    ISSN: 2090-0252
    URL: Article
    DOI: 10.4061/2011/792070
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2011
    detail.hit.zdb_id: 2573333-3
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  • 3
    Online Resource
    Online Resource
    Therapeutic Potential of α-Synuclein Evolvability for Autosomal Recessive Parkinson’s Disease
    Hindawi Limited ; 2021
    In:  Parkinson's Disease Vol. 2021 ( 2021-11-23), p. 1-11
    Details
    In: Parkinson's Disease, Hindawi Limited, Vol. 2021 ( 2021-11-23), p. 1-11
    Abstract: The majority of Parkinson’s disease (PD) is sporadic in elderly and is characterized by α-synuclein (αS) aggregation and other alterations involving mitochondria, ubiquitin-proteasome, and autophagy. The remaining are familial PD associated with gene mutations of either autosomal dominant or recessive inheritances. However, the former ones are similar to sporadic PD, and the latter ones are accompanied by impaired mitophagy during the reproductive stage. Since no radical therapies are available for PD, the objective of this paper is to discuss a mechanistic role for amyloidogenic evolvability, a putative physiological function of αS, among PD subtypes, and the potential relevance to therapy. Presumably, αS evolvability might benefit familial PD due to autosomal dominant genes and also sporadic PD during reproduction, which may manifest as neurodegenerative diseases through antagonistic pleiotropy mechanism in aging. Indeed, there are some reports describing that αS prevents apoptosis and mitochondrial alteration under the oxidative stress conditions, notwithstanding myriads of papers on the neuropathology of αS. Importantly, β-synuclein (βS), the nonamyloidogenic homologue of αS, might buffer against evolvability of αS protofibrils associated with neurotoxicity. Finally, it is intriguing to predict that increased αS evolvability through suppression of βS expression might protect against autosomal recessive PD. Collectively, further studies are warranted to better understand αS evolvability in PD pathogenesis, leading to rational therapy development.
    Type of Medium: Online Resource
    ISSN: 2042-0080 , 2090-8083
    URL: Article
    DOI: 10.1155/2021/6318067
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2021
    detail.hit.zdb_id: 2573854-9
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  • 4
    Online Resource
    Online Resource
    Motor and Nonmotor Symptoms of Parkinson’s Disease: Antagonistic Pleiotropy Phenomena Derived from α -Synuclein Evolvability?
    Hindawi Limited ; 2018
    In:  Parkinson's Disease Vol. 2018 ( 2018-11-22), p. 1-6
    Details
    In: Parkinson's Disease, Hindawi Limited, Vol. 2018 ( 2018-11-22), p. 1-6
    Abstract: Lewy body diseases, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as α -synuclein ( α S) and amyloid- β (A β ) in the brain. Based on the heterogeneity of protofibrillar AP forms in terms of structure and cytotoxicity, we recently proposed that APs might act as vehicles to deliver information regarding diverse internal and environmental stressors. Also, we defined evolvability to be an epigenetic phenomenon whereby APs are transgenerationally transmitted from parents to offspring to cope with future brain stressors in the offspring, likely benefitting the offspring. In this context, the main objective is to discuss whether NMS might be relevant to evolvability. According to this view, information regarding NMS may be transgenerationally transmitted by heterogeneous APs to offspring, preventing or attenuating the stresses related to such symptoms. On the other hand, NMS associated with Lewy body pathology might manifest through an aging-associated antagonistic pleiotropy mechanism. Given that NMS are not only specific to Lewy body diseases but also displayed in other disorders, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), these conditions might share common mechanisms related to evolvability. This might give insight into novel therapy strategies based on antagonistic pleiotropy rather than on individual NMS from which to develop disease-modifying therapies.
    Type of Medium: Online Resource
    ISSN: 2090-8083 , 2042-0080
    URL: Article
    DOI: 10.1155/2018/5789424
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2018
    detail.hit.zdb_id: 2573854-9
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  • 5
    Online Resource
    Online Resource
    Distinct Pattern of Microgliosis in the Olfactory Bulb of Neurodegenerative Proteinopathies
    Hindawi Limited ; 2017
    In:  Neural Plasticity Vol. 2017 ( 2017), p. 1-15
    Details
    In: Neural Plasticity, Hindawi Limited, Vol. 2017 ( 2017), p. 1-15
    Abstract: The olfactory bulb (OB) shows early neuropathological hallmarks in numerous neurodegenerative diseases, for example, in Alzheimer’s disease (AD) and Parkinson’s disease (PD). The glomerular and granular cell layer of the OB is characterized by preserved cellular plasticity in the adult brain. In turn, alterations of this cellular plasticity are related to neuroinflammation such as microglia activation, implicated in the pathogenesis of AD and PD, as well as frontotemporal lobe degeneration (FTLD). To determine microglia proliferation and activation we analyzed ionized calcium binding adaptor molecule 1 (Iba1) expressing microglia in the glomerular and granular cell layer, and the olfactory tract of the OB from patients with AD, PD dementia/dementia with Lewy bodies (PDD/DLB), and FTLD compared to age-matched controls. The number of Iba1 and CD68 positive microglia associated with enlarged amoeboid microglia was increased particularly in AD, to a lesser extent in FTLD and PDD/DLB as well, while the proportion of proliferating microglia was not altered. In addition, cells expressing the immature neuronal marker polysialylated neural cell adhesion molecule (PSA-NCAM) were increased in the glomerular layer of PDD/DLB and FTLD cases only. These findings provide novel and detailed insights into differential levels of microglia activation in the OB of neurodegenerative diseases.
    Type of Medium: Online Resource
    ISSN: 2090-5904 , 1687-5443
    URL: Article
    DOI: 10.1155/2017/3851262
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2017
    detail.hit.zdb_id: 2236872-3
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