Frontiers in Alzheimer’s disease therapeutics

Stone, Jennifer A.; Casadesús, Gemma; Gustaw-Rothenberg, Kasia; Siedlak, Sandra L.; Wang, Xinglong; Zhu, Xiongwei; Perry, George; Castellani, Rudy J.; Smith, Mark A.

doi:10.1177/2040622310382817

Cited by 28 publications

(17 citation statements)

References 163 publications

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“…Considerable research has focused on the neurotoxicity of beta amyloid peptides (Aβ) since they were identified in plaques from AD patients decades ago (Goate and Hardy, 2012; Holtzman et al, 2011; Selkoe, 1993), yet therapeutic studies targeting Aβ have yielded disappointing or counterproductive results (Aisen et al, 2011; Galimberti and Scarpini, 2011; Karran et al, 2011; Selkoe, 2011b; Stone et al, 2011). Among other things, impediments to progress in this arena might reflect uncertainty regarding the relevant Aβ species to target (Benilova et al, 2012), the use of inconsistent model systems or supraphysiologic Aβ peptide concentrations (Castellani and Smith, 2011; Waters, 2010), incomplete understanding of physiologic versus pathologic roles of Aβ and amyloid precursor protein (APP) (Chasseigneaux and Allinquant, 2012; Guo et al, 2012; Zhang et al, 2012), and incomplete consideration of alternative pathogenic mechanisms, particularly those affecting synapses (Chakroborty and Stutzmann, 2011).…”

Section: Introductionmentioning

confidence: 99%

Beta amyloid peptide plaques fail to alter evoked neuronal calcium signals in APP/PS1 Alzheimer's disease mice

Briggs

Schneider

Richardson

et al. 2013

Neurobiology of Aging

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Alzheimer’s disease (AD) is a multifactorial disorder of unknown etiology. Mechanistically, beta amyloid peptides (Aβ) and elevated Ca2+ have been implicated as proximal and likely interactive features of the disease process. We tested the hypothesis that proximity to Aβ plaque might exacerbate activity-dependent neuronal Ca2+ signaling in hippocampal pyramidal neurons from APPSWE/PS1M146V mice. Using combined approaches of whole cell patch clamp recording and 2-photon imaging of neuronal Ca2+ signals with thioflavin-S plaque labeling in hippocampal slices, we found no correlation between thioflavin-S labeled Aβ plaque proximity and Ca2+ responses triggered by ryanodine receptor (RyR) activation or action potentials in either dendrites or somata of AD mice, regardless of age. Baseline and RyR-stimulated spontaneous excitatory postsynaptic potentials also showed little difference in relation to Aβ plaque proximity. Consistent with previous studies, RyR-evoked Ca2+ release in APPSWE/PS1M146V mice was greater than in nontransgenic controls. Within the soma, RyR-evoked Ca2+ release was elevated in older APPSWE/PS1M146V mice compared with younger APPSWE/PS1M146V mice, but was still independent of plaque proximity. The results indicate that early Ca2+ signaling disruptions can become yet more severe with age through mechanisms independent of Aβ plaques, suggesting that alternative pathogenic mechanisms might contribute to AD-associated dysfunction.

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Section: Introductionmentioning

confidence: 99%

Beta amyloid peptide plaques fail to alter evoked neuronal calcium signals in APP/PS1 Alzheimer's disease mice

Briggs

Schneider

Richardson

et al. 2013

Neurobiology of Aging

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“…Since the loss of cholinergic activity is a major trait observed in AD, the current first‐line treatment for AD is acetylcholinesterase (AChE) inhibitors (Álvarez and Fuentes,2011; Farlow and Cummings;2007, Stone et al,2011) such as donepezil, rivastigmine, tacrine, and galantamine (Craig et al,2011; Seow and Gauthier,2007). The most widely prescribed drug for AD treatment is donepezil (Craig et al,2011; Tsuno,2009).…”

Section: Introductionmentioning

confidence: 99%

Combined administration of cerebrolysin and donepezil induces plastic changes in prefrontal cortex in aged mice

Alcántara-González

Mendoza-Perez

Zaragoza

et al. 2012

Synapse

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Cerebrolysin (Cbl) shows neurotrophic and neuroprotective properties while donepezil (Dnp) is a potent acetylcholinesterase (AChE) inhibitor, both drugs are prescribed for Alzheimer's disease (AD) treatment. Previous studies have shown that the Dnp and Cbl administered separately, modify dendritic morphology of neurons in the prefrontal cortex and hippocampus in senile rodents. Since the deficit of neurotrophic factor activity is implicated in the degeneration of cholinergic neurons of basal forebrain, a combination therapy of Dnp and Cbl has been tested recently in Alzheimer's patients. However, the plastic changes that may underlie this combined treatment have not yet been explored. We present here the effect of the combined administration of Cbl and Dnp on dendritic morphology in brain regions related to learning and memory in aged mice. The Golgi‐Cox staining protocol and Sholl analysis were used for studying dendritic changes. Cbl and Dnp were administrated daily for 2 months to 9‐months‐old mice. Locomotor activity was assessed, as well as the dendritic morphology of neurons in several limbic regions was analyzed. Results showed that Cbl and Dnp induced an increase in locomotor activity without synergistic effect. The Cbl or Dnp treatment modified the dendritic morphology of neurons from prefrontal cortex (PFC), dorsal hippocampus (DH), dentate gyrus (DG), and the shell of nucleus accumbens (NAcc). These changes show an increase in the total dendritic length and spine density, resulting in an improvement of dendritic arborization. Prominently, a synergistic effect of Cbl and Dnp was observed on branching order and total dendritic length of pyramidal neurons from PFC. These results suggest that Dnp and Cbl may induce plastic changes in a manner independent of each other, but could enhance their effect in target cells from PFC. Synapse 66:938–949, 2012. © 2012 Wiley Periodicals, Inc.

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“…Today, multiple therapies for AD are being studied [62,70,71]. The progress in the knowledge of the molecular characteristics of the disease and the availability of several animal models for study, it has open the boundaries to test and develop new therapies [61,62,72], for example, strategies for modifying AD progression include reducing neuroinflammation, metabolic approaches such as lipid-lowering agents, estrogen, antioxidants, anti-Aβ immunotherapy and recent neurotrophin-based approaches [62,69,72,73]. In this scenario, and given the importance and the temporality of mitochondrial damage in AD, we believe that mitochondrial-targeted therapeutic strategies are one of the most promising areas of interest.…”

Section: Improving Mitochondrial Health As a Valid Therapy For Admentioning

confidence: 99%

New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach

Pérez¹,

Jara²,

Muñoz‐Urrutia³

et al. 2016

Update on Dementia

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Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia. AD is characterized by brain presence of senile plaques, which are formed by aggregates of Aβ peptide and neurofibrillary tangles (NFTs), formed by pathological forms of tau protein. Evidence suggests that these elements affect neurons compromising energy supply, antioxidant response and synaptic activity. AD principally affects the memory and cognitive functions of the patients, and currently, successful strategies for diagnosis and early treatment are lacking. In this scenario, accumulative evidence suggests that mitochondrial dysfunction precedes the establishment of tau and Aβ pathology and contributes to synaptic degeneration observed in AD. Therefore, reducing mitochondrial injury may have beneficial effects for neuronal dysfunction and cognitive decline observed in AD patients. Interestingly, the examination of peripheral cells from AD patients also presents mitochondrial dysfunction, suggesting that tracking these mitochondrial defects in peripheral cells could be a potential mechanism of early diagnosis of AD. In this chapter, we analyse current evidence that suggests that mitochondrial injury is an important factor in the pathogenesis of AD and how studying this process could reveal new strategies to mitigate neurodegeneration and to develop new diagnostic methods for an early detection of AD.

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Frontiers in Alzheimer’s disease therapeutics

Cited by 28 publications

References 163 publications

Beta amyloid peptide plaques fail to alter evoked neuronal calcium signals in APP/PS1 Alzheimer's disease mice

Beta amyloid peptide plaques fail to alter evoked neuronal calcium signals in APP/PS1 Alzheimer's disease mice

Combined administration of cerebrolysin and donepezil induces plastic changes in prefrontal cortex in aged mice

New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach

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