Relation of Quantitative Indexes of Concurrent α-Synuclein Abnormalities to Clinical Outcome in Autopsy-Proven Alzheimer Disease

Irizarry, Michael C.; Sanders, J. B.; Hyman, Bradley T.; Wegesin, Domonick J.; Riba, Aliza; Brandt, Jason; Albert, Marilyn; Stern, Yaakov

doi:10.1001/archneur.63.2.226

Cited by 12 publications

(14 citation statements)

References 38 publications

(18 reference statements)

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“…There have been numerous clinicopathological studies attempting to correlate amyloid plaques with the cognitive deficits seen in AD (Blessed et al, 1968; Tomlinson et al, 1970; Duyckaerts et al, 1990, 1998; Berg et al, 1998; Gold et al, 2000; Mungas et al, 2001; Tiraboschi et al, 2002, 2004; Guillozet et al, 2003; Kraybill et al, 2005; Holtzer et al, 2006; Markesbery et al, 2006; Nelson et al, 2007a, 2009a; Beach et al, 2009; Sabbagh et al, 2010; Robinson et al, 2011). Apparent inconsistencies in the conclusions of these studies are due to differences in study cohorts, methodology used to classify plaque subcategories, plaque-counting techniques, and metrics used to assess cognitive deficits.…”

Section: Overview Of Neuropathological Changes In Admentioning

confidence: 99%

“…In contrast to the literature concerning amyloid plaques, a large number of studies have arrived at a common finding, namely, there is a strong link between neocortical NFTs and cognitive decline (Tomlinson et al, 1970; Duyckaerts et al, 1990, 1997, 1998; Mckee et al, 1991; Arriagada et al, 1992; Bierer et al, 1995; Davis et al, 1995; Dickson et al, 1995; Nagy et al, 1995, 1999; Cummings et al, 1996; Berg et al, 1998; Grober et al, 1999; Sabbagh et al, 1999; Gold et al, 2000; Mungas et al, 2001; Riley et al, 2002; Silver et al, 2002; Tiraboschi et al, 2002; Guillozet et al, 2003; Bennett et al, 2004; Kraybill et al, 2005; Holtzer et al, 2006; Markesbery et al, 2006; Koepsell et al, 2008; Whitwell et al, 2008; Beach et al, 2009; Brayne et al, 2009; Giannakopoulos et al, 2009; Sabbagh et al, 2010; Robinson et al, 2011). It should be noted that outside of frontotemporal lobar degeneration (FTLD), one does not see widespread cortical NFTs without abundant plaque pathology.…”

Section: Overview Of Neuropathological Changes In Admentioning

confidence: 99%

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Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models

et al. 2014

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The goal of this review is to discuss how behavioral tests in mice relate to the pathological and neuropsychological features seen in human Alzheimer's disease (AD), and present a comprehensive analysis of the temporal progression of behavioral impairments in commonly used AD mouse models that contain mutations in amyloid precursor protein (APP). We begin with a brief overview of the neuropathological changes seen in the AD brain and an outline of some of the clinical neuropsychological assessments used to measure cognitive deficits associated with the disease. This is followed by a critical assessment of behavioral tasks that are used in AD mice to model the cognitive changes seen in the human disease. Behavioral tests discussed include spatial memory tests [Morris water maze (MWM), radial arm water maze (RAWM), Barnes maze], associative learning tasks (passive avoidance, fear conditioning), alternation tasks (Y-Maze/T-Maze), recognition memory tasks (Novel Object Recognition), attentional tasks (3 and 5 choice serial reaction time), set-shifting tasks, and reversal learning tasks. We discuss the strengths and weaknesses of each of these behavioral tasks, and how they may correlate with clinical assessments in humans. Finally, the temporal progression of both cognitive and non-cognitive deficits in 10 AD mouse models (PDAPP, TG2576, APP23, TgCRND8, J20, APP/PS1, TG2576 + PS1 (M146L), APP/PS1 KI, 5×FAD, and 3×Tg-AD) are discussed in detail. Mouse models of AD and the behavioral tasks used in conjunction with those models are immensely important in contributing to our knowledge of disease progression and are a useful tool to study AD pathophysiology and the resulting cognitive deficits. However, investigators need to be aware of the potential weaknesses of the available preclinical models in terms of their ability to model cognitive changes observed in human AD. It is our hope that this review will assist investigators in selecting an appropriate mouse model, and accompanying behavioral paradigms to investigate different aspects of AD pathology and disease progression.

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Section: Overview Of Neuropathological Changes In Admentioning

confidence: 99%

Section: Overview Of Neuropathological Changes In Admentioning

confidence: 99%

Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models

et al. 2014

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“…The association between the occurrence of Lewy bodies in AD patients and disease severity is under debate. Some authors do not find any correlation; other papers are indicating that there is a link between the mixed pathology and an accelerated disease progression [91][92][93][94][95].…”

Section: Alpha Synuclein and Alzheimer's Diseasementioning

confidence: 96%

Is alpha-Synuclein Pathology a Target for Treatment of Neurodegenerative Disorders?

Windisch¹,

Wolf²,

Hutter‐Paier³

et al. 2007

CAR

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Alpha-synuclein is the main constituent of intra-neuronal Lewy bodies, which are characteristic of Parkinson's disease, but aggregates are also found as axonal inclusions. Alpha-synuclein pathology is found together with beta-amyloid plaques and neurofibrillary tangles in Alzheimer's disease and other neurodegenerative disorders. In spite of the fact that the biological function of this synaptic protein is not known so far, there is an increasing body of evidence indicating an interaction with amyloid peptides, but also with tau-hyperphosphorylation. A high proportion of alpha-synuclein purified from Lewy bodies is phosphorylated on Ser129. There are still different opinions about the toxicity of the alpha-synuclein aggregates. Alpha-synuclein seems to influence different intracellular signaling pathways which are in direct relation to defense mechanisms against reactive oxygen species or apoptosis. It is obvious that overproduction of alpha-synuclein, but also different mutations, are inducing the formation of aggregates. Because of the possible link to neurodegeneration, different attempts have been made to counteract alpha-synuclein aggregation. An interesting approach is utilizing beta-synuclein, a biological factor, with an aminoacid sequence closely resembling that of alpha-synuclein. Proof of concept studies indicated that overexpression of beta-synuclein is able to counteract alpha-synuclein aggregation in a transgenic animal model, while also ameliorating functional deficits. As an alternative approach, the use of low molecular beta-synuclein N-terminal peptide derivatives has been considered. Several of these structures displayed clear neuroprotective activities in tissue culture models of neurodegeneration, including beta-amyloid toxicity. Therefore it has been speculated that these compounds might have a broad therapeutic efficacy in different neurodegenerative disorders. A proof of concept study in hAPP-transgenic animals resulted in a highly significant decrease in beta-amyloid plaque load, an increase in soluble beta-amyloid peptides and a decrease in insoluble forms. There was also significant improvement of cognitive deficits in this APP transgenic mouse model following intranasal but also peripheral treatment with three of these compounds. From this study it is concluded that the observed effects of the peptides derived from beta-synuclein N-terminus are depending on both, a direct interaction with aggregation of proteins, but also with stimulation of anti-apoptotic and anti-oxidative intracellular signaling pathways.

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“…Holtzer et al [36] PD Aggregated a-synuclein in primary mesencephalic neuron-glia culture activated microglia that enhanced dopaminergic neurodegeneration Zhang et al [37] Autoantibodies MS Autoantibodies to myelin basic protein were detected in sera from patients with MS Hedegaard et al [38] AD Autoantibodies to b-amyloid are common in AD Kellner et al [39] ALS Autoantibodies to neurofilament are found in patients with ALS Couratier et al [40] PD Autoantibodies to a-synuclein were detected in patients with PD, particularly the familial form…”

Section: Parallels Between Ms and Neurodegenerative Diseasesmentioning

confidence: 99%

Targeting Progressive Neuroaxonal Injury

et al. 2011

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Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuroaxonal injury, suggesting a common pathophysiological pathway. Identification and development of neuroprotective therapies for such diseases has proven a major challenge, particularly because of an already substantial neuroaxonal compromise at the time of initial onset of clinical symptoms. Methods for early identification of neurodegeneration are therefore vital to ensure that neuroprotective therapies are applied as early as possible. Recent investigations have enhanced our understanding of the role of neuroaxonal injury in multiple sclerosis (MS). As MS generally manifests earlier in life and can be diagnosed much earlier in the course of the disease than the above-mentioned 'classic' neurodegenerative diseases, it is possible that MS could be used as a model disease to study degeneration and regeneration of the CNS. The mechanism of neuroaxonal injury in MS is believed to be inflammation-led neurodegeneration; however, the reverse may also be true (i.e. neuroaxonal degeneration may precede inflammation). Animal models of PD, AD and ALS have shown that it is likely that most cases of disease are due to initial inflammation, followed by a degenerative process, providing a parallel between MS and the classic neurodegenerative diseases. Other common factors between MS and the neurodegenerative diseases include iron and mitochondrial dysregulation, abnormalities in α-synuclein and tau protein, and a number of immune mediators. Conventional MRI techniques, using markers such as T2-weighted lesions, gadolinium-enhancing lesions and T1-weighted hypointensities, are readily available and routinely used in clinical practice; however, the utility of these MRI measures to predict disease progression in MS is limited. More recently, MRI techniques that provide more pathology-specific data have been applied in MS studies, including magnetic resonance spectroscopy, magnetization transfer ratio and myelin water imaging. Optical coherence tomography (OCT) is a non-MRI technique that quantifies optic nerve integrity and retinal ganglion cell loss as markers of neuroaxonal injury; more research is needed to evaluate whether information obtained from OCT is a reliable marker of axonal injury and long-term disability in MS. Using these advanced techniques, it may become possible to follow degeneration and regeneration longitudinally in patients with MS and to better differentiate the effects of drugs under investigation. Currently available immune-directed therapies that are approved by the US FDA for the first-line treatment of MS (interferon-β and glatiramer acetate) have been shown to decelerate the inflammatory process in MS; however, such therapy is less effective in preventing the progression of the disease and neuroaxonal injury. The use of MS as a clinical model to study modulation of neuroaxonal injury in the brain could have direct implications for the deve...

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Relation of Quantitative Indexes of Concurrent α-Synuclein Abnormalities to Clinical Outcome in Autopsy-Proven Alzheimer Disease

Cited by 12 publications

References 38 publications

Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models

Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models

Is alpha-Synuclein Pathology a Target for Treatment of Neurodegenerative Disorders?

Targeting Progressive Neuroaxonal Injury

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