Are Biomarkers Valid as Surrogates for Treatment Effects in Alzheimer’s Disease?

2009 ◽  
Vol 4 (1) ◽  
pp. 13
Author(s):  
Philip Scheltens ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Efficacy ◽  
Laboratory Tests ◽  
Neuropsychological Testing ◽  
Neuronal Loss ◽  
Therapeutic Strategies ◽  
Disease Course ◽  
Amyloid Beta Protein ◽  
The Brain

Diagnosis of Alzheimer’s disease (AD), the most common form of dementia, involves neuropsychological testing, limited laboratory tests and brain imaging. Current therapeutic options for AD are symptomatic treatments that target dysfunctional neurotransmitters associated with the disorder. Recent research has focused on therapeutic strategies that inhibit the production and aggregation of amyloid beta protein (Aβ) in plaques and increase its clearance from the brain. Such strategies are likely to be most effective at pre-clinical stages of the disease, before widespread synaptic and neuronal loss occurs. Thus, there is a need for biomarkers that predict disease course and outcome and monitor disease progression and treatment efficacy. The development of such biomarkers for AD is critical to translating the efficacy of new therapies.

scholarly journals Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 6071
Author(s):  
Suzanne Gascon ◽  
Jessica Jann ◽  
Chloé Langlois-Blais ◽  
Mélanie Plourde ◽  
Christine Lavoie ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factors ◽  
Signaling Pathways ◽  
Brain Structures ◽  
Therapeutic Strategies ◽  
Native Proteins ◽  
Receptor Sites ◽  
The Brain

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

scholarly journals Ceramide and Related-Sphingolipid Levels Are Not Altered in Disease-Associated Brain Regions of APPSLand APPSL/PS1M146LMouse Models of Alzheimer's Disease: Relationship with the Lack of Neurodegeneration?

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Laurence Barrier ◽  
Bernard Fauconneau ◽  
Anastasia Noël ◽  
Sabrina Ingrand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Neuronal Death ◽  
Time Course ◽  
Neuronal Loss ◽  
Brain Regions ◽  
App Processing ◽  
Ceramide Accumulation ◽  
The Brain

There is evidence linking sphingolipid abnormalities, APP processing, and neuronal death in Alzheimer's disease (AD). We previously reported a strong elevation of ceramide levels in the brain of the APPSL/PS1Ki mouse model of AD, preceding the neuronal death. To extend these findings, we analyzed ceramide and related-sphingolipid contents in brain from two other mouse models (i.e., APPSLand APPSL/PS1M146L) in which the time-course of pathology is closer to that seen in most currently available models. Conversely to our previous work, ceramides did not accumulate in disease-associated brain regions (cortex and hippocampus) from both models. However, the APPSL/PS1Ki model is unique for its drastic neuronal loss coinciding with strong accumulation of neurotoxic Aβisoforms, not observed in other animal models of AD. Since there are neither neuronal loss nor toxic Aβspecies accumulation in APPSLmice, we hypothesized that it might explain the lack of ceramide accumulation, at least in this model.

scholarly journals IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

2016 ◽  
Vol 113 (19) ◽  
pp. E2705-E2713 ◽  
Author(s):  
Amy K. Y. Fu ◽  
Kwok-Wang Hung ◽  
Michael Y. F. Yuen ◽  
Xiaopu Zhou ◽  
Deejay S. Y. Mak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Innate Immune Response ◽  
Memory Loss ◽  
Neuronal Loss ◽  
Innate Immune ◽  
Therapeutic Role ◽  
Potential Therapeutic Role ◽  
The Brain

Alzheimer’s disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.

scholarly journals GPCR19 regulates P2X7R-mediated NLRP3 inflammasomal activation of microglia by Amyloid β in Alzheimer’s diseases

2020 ◽  
Author(s):  
Jahirul Islam ◽  
Jung-Ah Cho ◽  
Ju-yong Kim ◽  
Kyung-Sun Park ◽  
Young-Jae koh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nlrp3 Inflammasome ◽  
Memory Function ◽  
Scavenger Receptor ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Priming Phase ◽  
5Xfad Mice ◽  
The Brain

Abstract Amyloid β (Aβ) and/or ATP activates NLRP3 inflammasome (N3I) by P2 × 7R ion channel of microglia, which is crucial in neuroinflammation shown in Alzheimer’s disease (AD). Due to polymorphisms, subtypes, and ubiquitous expression of P2 × 7R, inhibition of P2 × 7R has not been effective for AD. We first report that GPCR19 is a prerequisite for P2 × 7R-mediated N3I activation and Taurodeoxycholate (TDCA), a GPCR19 ligand, inhibited the priming phase of N3I activation, suppressed P2 × 7R expression and P2 × 7R-mediated Ca++ mobilization, and N3I oligomerization which is essential for production of IL-1β/IL-18. Further, TDCA increased expression of scavenger receptor (SR) A, enhanced phagocytosis of Aβ, and decreased Aβ plaque numbers in the brain of 5x Familial Alzheimer’s disease (5xFAD) mice. TDCA also reduced microgliosis, prevented neuronal loss, and improved memory function of 5xFAD mice. The pleiotropic roles of GPCR19 in P2 × 7-mediated N3I activation suggest that targeting GPCR19 might resolve neuroinflammation in AD patients.

scholarly journals Human brain organoids in Alzheimer’s disease

Organoid ◽  
2021 ◽  
Vol 1 ◽  
pp. e5
Author(s):  
You Jung Kang ◽  
Hansang Cho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Damage ◽  
Three Dimensional ◽  
Neuronal Loss ◽  
Model Systems ◽  
Key Characteristics ◽  
Brain Organoid ◽  
Human Brains ◽  
The Brain

Alzheimer’s disease (AD) is a progressive neurological disorder that typically involves neuronal damage leading to the deterioration of cognitive and essential body functions in aging brains. Major signatures of AD pathology include the deposition of amyloid plaques and neurofibrillary tangles, disruption of the blood-brain barrier, and induction of hyper-activated proinflammation in the brain, leading to synaptic impairment and neuronal loss. However, conventional pharmacotherapeutic modalities merely alleviate symptoms, but do not cure AD, partly because drug screening has used model systems with limited accuracy in terms of reflecting AD pathology in human brains. In this regard, several AD organoids have received substantial attention as alternatives to AD animal models. In this review, we summarize the key characteristics required for the generation of a pathologically relevant AD brain organoid. We also overview major experimental organoid models of AD brains, such as spheroids, three-dimensional (3D) bioprinted constructs, and 3D brain-on-chips, and discuss their strengths and weaknesses for AD research. This review will provide valuable information that will inspire future efforts to engineer authentic AD organoids for the study of AD pathology and for the discovery of novel AD therapeutic strategies.

scholarly journals Biomarkers for Alzheimer’s Disease Early Diagnosis

2020 ◽  
Vol 10 (3) ◽  
pp. 114 ◽  
Author(s):  
Eva Ausó ◽  
Violeta Gómez-Vicente ◽  
Gema Esquiva
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Loss ◽  
Diagnostic Tools ◽  
Csf Biomarkers ◽  
Diagnosis And Prognosis ◽  
Positron Emission ◽  
The Central Nervous System ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain

Alzheimer’s disease (AD) is the most common cause of dementia, affecting the central nervous system (CNS) through the accumulation of intraneuronal neurofibrillary tau tangles (NFTs) and β-amyloid plaques. By the time AD is clinically diagnosed, neuronal loss has already occurred in many brain and retinal regions. Therefore, the availability of early and reliable diagnosis markers of the disease would allow its detection and taking preventive measures to avoid neuronal loss. Current diagnostic tools in the brain, such as magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, and cerebrospinal fluid (CSF) biomarkers (Aβ and tau) detection are invasive and expensive. Brain-secreted extracellular vesicles (BEVs) isolated from peripheral blood have emerged as novel strategies in the study of AD, with enormous potential as a diagnostic evaluation of therapeutics and treatment tools. In addition; similar mechanisms of neurodegeneration have been demonstrated in the brain and the eyes of AD patients. Since the eyes are more accessible than the brain, several eye tests that detect cellular and vascular changes in the retina have also been proposed as potential screening biomarkers. The aim of this study is to summarize and discuss several potential markers in the brain, eye, blood, and other accessible biofluids like saliva and urine, and correlate them with earlier diagnosis and prognosis to identify individuals with mild symptoms prior to dementia.

scholarly journals Soluble forms of tau are toxic in Alzheimer’s disease

2012 ◽  
Vol 3 (3) ◽  
Author(s):  
Katherine Kopeikina ◽  
Bradley Hyman ◽  
Tara Spires-Jones
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Neuronal Death ◽  
Therapeutic Strategies ◽  
The Brain

AbstractAccumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer’s disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer’s disease and other tauopathies.

Modulation of ϐ-amyloid production and fibrillization

2001 ◽  
Vol 67 ◽  
pp. 1-14 ◽  
Author(s):  
David Allsop ◽  
Lance J. Twyman ◽  
Yvonne Davies ◽  
Susan Moore ◽  
Amber York ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibrils ◽  
Senile Plaques ◽  
Neurofibrillary Tangle ◽  
Neuronal Loss ◽  
Brain Parenchyma ◽  
Amino Acid Peptide ◽  
Close Relatives ◽  
The Brain

Alzheimer's disease (AD) is the most common cause of dementia in old age and presently affects an estimated 4 million people in the U.S.A. and 0.75 million people in the U.K. It is a relentless, degenerative brain disease, characterized by progressive cognitive impairment. In the final stages of the disease, patients are often bedridden, doubly incontinent and unable to speak or to recognize close relatives. Pathological changes of Alzheimer's disease include extensive neuronal loss and the presence of numerous neurofibrillary tangles and senile plaques in the brain. The senile plaques contain amyloid fibrils derived from a 39-43-amino-acid peptide referred to as ϐ-amyloid or Aϐ. The basic theory of the so-called 'amyloid hypothesis' is that the deposition of aggregated forms of Aϐ in the brain parenchyma triggers a pathological cascade of events that leads to neurofibrillary tangle formation, neuronal loss and the associated dementia [1]. Here we discuss progress towards the identification of inhibitors of Aϐ production and fibrillization.

GINKGETIN AMELIORATES NEUROPATHOLOGICAL CHANGES IN APP/PS1 TRANSGENICAL MICE MODEL

2015 ◽  
pp. 1-6
Author(s):  
Y.-Q. Zeng ◽  
Y.-J. Wang ◽  
X.-F. Zhou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Biological Properties ◽  
Amyloid Angiopathy ◽  
Amyloid Beta Protein ◽  
Mice Model ◽  
Cerebral Microhemorrhage ◽  
The Brain

The extracellular accumulation of amyloid beta protein (Aβ), reactive gliosis and cerebral amyloid angiopathy (CAA) play critical roles in the pathogenesis of Alzheimer’s disease (AD). Ginkgetin, a biflavone isolated from Ginkgo biloba leaves, was previously reported to exhibit strong neuroprotection against cytotoxic insults induced by oxidative stress and amyloid beta, but it remains unclear whether ginkgetin has therapeutic effect on Alzheimer’s disease (AD) in vivo. In the present study, we investigated 9 months treatment effects of ginkgetin diet in APP/PS1 mice. Our results show that ginkgetin can significantly reduce plasma Aβ levels 59% and Aβ plaque 51% in the brain of APP/PS1 transgenic mice (P<0.05), effectively inhibits cerebral microhemorrhage 69% (P<0.05), significantly decreases astrogliosis 50% and ameliorate inflammation (P<0.05), exhibits several biological properties for AD.

scholarly journals Spatiotemporal activation of the C/EBPβ/δ-secretase axis regulates the pathogenesis of Alzheimer’s disease

2018 ◽  
Vol 115 (52) ◽  
pp. E12427-E12434 ◽  
Author(s):  
Hualong Wang ◽  
Xia Liu ◽  
Shengdi Chen ◽  
Keqiang Ye
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Dependent Manner ◽  
Chronic Neuroinflammation ◽  
Factor C ◽  
The Brain ◽  
Ad Mouse Model

Alzheimer’s disease (AD) neuropathological hallmarks include senile plaques with aggregated amyloid beta as a major component, neurofibrillary tangles (NFT) containing truncated and hyperphosphorylated Tau, extensive neuronal loss, and chronic neuroinflammation. However, the key molecular mechanism that dominates the pathogenesis of AD remains elusive for AD. Here we show that the C/EBPβ/δ-secretase axis is activated in an age-dependent manner in different brain regions of the 3×Tg AD mouse model, elevating δ-secretase–truncated APP and Tau proteolytic truncates and promoting senile plaques and NFT formation in the brain, associated with gradual neuronal loss and chronic neuroinflammation. Depletion of inflammatory cytokine-regulated transcription factor C/EBPβ from 3×Tg mice represses APP, Tau, and δ-secretase expression, which subsequently inhibits APP and Tau cleavage, leading to mitigation of AD pathologies. Knockout of δ-secretase from 3×Tg mice strongly blunts AD pathogenesis. Consequently, inactivation of the C/EBPβ/δ-secretase axis ameliorates cognitive dysfunctions in 3×Tg mice by blocking APP and Tau expression and their pathological fragmentation. Thus, our findings support the notion that C/EBPβ/δ-secretase axis plays a crucial role in AD pathogenesis.

Sign in / Sign up

Export Citation Format

Share Document