The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

Alzheimer s Research & Therapy, Год журнала: 2020, Номер 12(1)

Опубликована: Март 2, 2020

Abstract Background Synapse damage and loss are fundamental to the pathophysiology of Alzheimer’s disease (AD) lead reduced cognitive function. The goal this review is address challenges forging new clinical development approaches for AD therapeutics that can demonstrate reduction synapse or loss. key points include following: a downstream effect amyloidosis, tauopathy, inflammation, other mechanisms occurring in AD. correlates most strongly with decline because synaptic function underlies performance. Compounds halt reduce have strong rationale as treatments Biomarkers measure degeneration patients will facilitate such drugs. ability methods sensitively density brain living patient through vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations proteins (e.g., neurogranin synaptotagmin) cerebrospinal fluid (CSF), functional imaging techniques quantitative electroencephalography (qEEG) provides compelling case use these types measurements biomarkers quantify trials Conclusion A number emerging able injury may correlate These hold promise both diagnostics measurement therapeutic successes.

Язык: Английский

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Protein phosphorylation in neurodegeneration: friend or foe?

Frontiers in Molecular Neuroscience, Год журнала: 2014, Номер 7

Опубликована: Май 13, 2014

Protein misfolding and aggregation is a common hallmark in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's (PD), fronto-temporal dementia (FTD). In these the of specific proteins occurs alongside neuronal degeneration somewhat brain areas, depending on disorder stage disease. However, we still do not fully understand mechanisms governing protein aggregation, whether this constitutes protective or detrimental process. PD, alpha-synuclein (aSyn) forms aggregates, known as Lewy bodies, phosphorylated at serine 129. Other residues have also been shown to be phosphorylated, but significance phosphorylation biology pathophysiology controversial. AD FTD, hyperphosphorylation tau causes its aggregation. Again, our understanding precise consequences limited. Through use variety model organisms technical approaches, are now gaining stronger insight into effects behaviour proteins. review, cover recent findings field discuss how targeting events might used for therapeutic intervention devastating diseases nervous system.

Язык: Английский

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Activity-Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers

Journal of Neuroscience, Год журнала: 2014, Номер 34(17), С. 6084 - 6097

Опубликована: Апрель 23, 2014

Tau is a microtubule-associated protein well known for its stabilization of microtubules in axons. Recently, it has emerged that tau participates synaptic function as part the molecular pathway leading to amyloid-beta (Aβ)-driven synaptotoxicity context Alzheimer's disease. Here, we report implication profound functional modification associated with plasticity. By exposing murine cultured cortical neurons pharmacological activation, induced translocation endogenous from dendritic postsynaptic compartment. We observed similar fraction acute hippocampal slices subjected long-term potentiation. When performed live confocal microscopy on transfected human-tau-GFP, visualized an activity-dependent accumulation density. Coprecipitation using phalloidin revealed interacts most predominant cytoskeletal component present, filamentous actin. Finally, when exposed cultures 100 n m human synthetic Aβ oligomers (Aβo's) 15 min, mislocalization into spines under resting conditions and abrogated subsequent translocation. These changes dynamics may rely difference between physiological pathological phosphorylation tau. Together, these results suggest intense activity drives density excitatory synapses Aβo-driven spine deserves further investigation key event toward neurodegenerative diseases.

Язык: Английский

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Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits

Frontiers in Neuroscience, Год журнала: 2018, Номер 12

Опубликована: Июнь 8, 2018

Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent diseases in elderly population worldwide. A growing body epidemiological studies suggest that people with T2DM at a higher risk developing AD. Likewise, AD brains less capable glucose uptake from surroundings resembling condition brain insulin resistance. Pathologically is characterized by extracellular plaques A intracellular neurofibrillary tangles hyperphosphorylated tau. T2DM, on other hand metabolic disorder hyperglycemia In this review we have discussed how Insulin resistance directly exacerbates tau pathologies elucidated pathophysiological traits synaptic dysfunction, inflammation autophagic impairments common to both indirectly impact functions neurons. Elucidation underlying pathways connect these will be immensely valuable for designing novel drug targets disease.

Язык: Английский

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Emerging Concepts in Alzheimer's Disease

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2014, Номер 10(1), С. 291 - 319

Опубликована: Ноя. 11, 2014

Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) is most common neuropathologic substrate dementia. It characterized by synapse loss (predominantly within neocortex) as well deposition certain distinctive lesions (the result protein misfolding) throughout brain. The latter include senile plaques, composed mainly an amyloid (Aβ) core and a neuritic component; neurofibrillary tangles, predominantly hyperphosphorylated tau; cerebral angiopathy, microangiopathy affecting both cortical capillaries arterioles resulting from Aβ their walls or (in case capillaries) immediately adjacent brain parenchyma. In this article, I discuss hypothesized role these play in causing dysfunction, CSF neuroimaging biomarkers (for dementia) that are especially relevant immunotherapeutic approaches being developed to remove addition, address neuropathology characterizing sequelae new AD/SDAT therapies helping validate disease. Comorbidity various types cerebrovascular disease major theme research, cognitive impairment develops oldest old, who vulnerable ischemic hemorrhagic lesions.

Язык: Английский

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