History and progress of hypotheses and clinical trials for Alzheimer’s disease

Li, Peipei; Xie, Yi; Meng, Xiaoyan; Kang, Jian-Sheng

doi:10.1038/s41392-019-0063-8

Cited by 492 publications

(398 citation statements)

References 459 publications

(494 reference statements)

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“…Among the different forms of dementia, Alzheimer's disease (AD) is the most common (60-70% of cases) and currently affects 47 million people worldwide [5][6][7]. Its prevalence rises exponentially with age and, due to increasing lifespan, it has been predicted to double every 20 years, causing a huge burden on healthcare costs [5,8]. AD is characterized by irreversible and progressive brain atrophy, loss of memory, and cognition.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Role of Dietary Supplementation with Omega-3 Fatty Acids in the Presence of Basal Forebrain Cholinergic Neurons Degeneration in Aged Mice

Cutuli

Landolfo

Decandia

et al. 2020

IJMS

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As major components of neuronal membranes, omega-3 polyunsaturated fatty acids (n-3 PUFA) exhibit a wide range of regulatory functions. Recent human and animal studies indicate that n-3 PUFA may exert beneficial effects on aging processes. Here we analyzed the neuroprotective influence of n-3 PUFA supplementation on behavioral deficits, hippocampal neurogenesis, volume loss, and astrogliosis in aged mice that underwent a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valid model to mimic a key component of the cognitive deficits associated with dementia. Aged mice were supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks and then cholinergically depleted with mu-p75-saporin immunotoxin. Two weeks after lesioning, mice were behaviorally tested to assess anxious, motivational, social, mnesic, and depressive-like behaviors. Subsequently, morphological and biochemical analyses were performed. In lesioned aged mice the n-3 PUFA pre-treatment preserved explorative skills and associative retention memory, enhanced neurogenesis in the dentate gyrus, and reduced volume and VAChT levels loss as well as astrogliosis in hippocampus. The present findings demonstrating that n-3 PUFA supplementation before cholinergic depletion can counteract behavioral deficits and hippocampal neurodegeneration in aged mice advance a low-cost, non-invasive preventive tool to enhance life quality during aging.

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Section: Introductionmentioning

confidence: 99%

Neuroprotective Role of Dietary Supplementation with Omega-3 Fatty Acids in the Presence of Basal Forebrain Cholinergic Neurons Degeneration in Aged Mice

Cutuli

Landolfo

Decandia

et al. 2020

IJMS

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“…Amyloid-β plaque deposition, albeit slight controversy, is still to this day considered the main pathology of AD [3,[71][72][73]. Reduction in Aβ plaques in transgenic mouse models were regarded as an endpoint for the studies of AD [74,75].…”

Section: Discussionmentioning

confidence: 99%

Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

Angel

Volkman

Royal

et al. 2020

IJMS

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-α, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-β plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD. cleavage into smaller subunits that form the active caspase heterodimer [6]. Caspases have been implicated in numerous diseases as their function leads to apoptosis and cell death [7,8]. Elucidating their roles in those diseases has been the subject of many years of research around the world.Caspase-6 belongs to the pro-apoptotic executioner caspase group and is activated by a series of upstream activators, amongst which are caspase-3 and caspase-1 [9,10]. Caspase-6 was shown to mediate several non-apoptotic processes, such as facilitating axonal pruning during development [11,12]. Cleavage by caspase-6 of the mutant huntingtin gene was shown to be a prerequisite for neuronal dysfunction and degeneration, and therefore, exacerbates neurodegeneration in Huntington's disease [8,13]. Caspase-6 activity is associated with AD pathological lesions and is present at the early stages of tangle formation [14]. The pro-apoptotic protein p53 is increased in AD brains and p53 directly up-regulates the transcription of caspase-6 [15], resulting in a significant increase in caspase-6 mRNA in human AD brains. Caspase-6 cleaves the APP at a specific site, creating the toxic small peptide C31, a potent inducer of apoptosis in cultured neuroblastoma cells [4]. Thus, caspase-6 is considered to be an up-stream modulator of AD pathogenesis, and as a result, a viable therapeutic target for the treatment of AD [8].Caspase-6 knock-out (KO) neurons are protected against excitotoxicity, trophic factor deprivation, and myelin induced axonal degeneration [16]. Caspase-6 KO mice were first described by Uribe et al. [16]. Research using these mice showed a reduction in the inflammatory response and...

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“…Many hypotheses have been proposed to underlie the development of AD, including i) amyloid beta aggregation, ii) tau hyperphosphorylation, iii) neuroinflammation, iv) neurotransmitter dysfunction, v) mitochondria dysfunction, vi) glucose metabolism, vii) vascular dysfunction and viii) viral infection [214][215][216][217] . These hypotheses have generated many new compounds, none of which showed efficacy in slowing cognitive decline or improving global functioning 214,216 . Arc appears a good therapeutic candidate for AD, because of its involvement in amyloid beta production, tau phosphorylation, neuroinflammation and neurotransmission.…”

Section: Arc Controls Synaptic Plasticity and Intrinsic Excitabilitymentioning

confidence: 99%

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease

Leung

Gwq

VanDongen

2019

Preprint

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The immediate-early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Arc protein is localized to excitatory synapses, where it controls AMPA receptor endocytosis, and to the nucleus, where it associates with Tip60, a subunit of a chromatin modifying complex. Here we show that Arc interacts with dynamic chromatin loops and associates with histone markers for active enhancers and transcription in cultured hippocampal neurons. When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes. Many gene families were affected by the absence of Arc, most notably those associated with synaptic function, neuronal plasticity, intrinsic excitability (channels, receptors, transporters), and signaling pathways (transcription factors/regulators). Interestingly, about 100 genes whose activitydependent expression level depends on Arc are associated with the pathophysiology of Alzheimer's disease, suggesting a critical role for Arc in the development of neurodegenerative disorders. When endogenous Arc expression was induced in a non-neuronal cell line (HEK293T), the transcription of many neuronal genes was increased, suggesting Arc can control expression in the absence of activated signaling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and a significant factor underlying the pathophysiology Alzheimer's disease.

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History and progress of hypotheses and clinical trials for Alzheimer’s disease

Cited by 492 publications

References 459 publications

Neuroprotective Role of Dietary Supplementation with Omega-3 Fatty Acids in the Presence of Basal Forebrain Cholinergic Neurons Degeneration in Aged Mice

Neuroprotective Role of Dietary Supplementation with Omega-3 Fatty Acids in the Presence of Basal Forebrain Cholinergic Neurons Degeneration in Aged Mice

Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease

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