Molecular and Imaging Biomarkers in Alzheimer’s Disease: A Focus on Recent Insights

Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly, affecting millions of people worldwide and clinically characterized by a progressive and irreversible cognitive decline. The rapid increase in the incidence of AD highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods rely on measures of amyloid-β (Aβ), phosphorylated (p-tau) and total tau (t-tau) protein levels in the cerebrospinal fluid (CSF) aided by advanced neuroimaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI). However, the invasiveness of these procedures and the high cost restrict their utilization. Hence, biomarkers from biological fluids obtained using non-invasive methods and novel neuroimaging approaches provide an attractive alternative for the early diagnosis of AD. Such biomarkers may also be helpful for better understanding of the molecular mechanisms underlying the disease, allowing differential diagnosis or at least prolonging the pre-symptomatic stage in patients suffering from AD. Herein, we discuss the advantages and limits of the conventional biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques.

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Imaging and Molecular Mechanisms of Alzheimer’s Disease: A Review

International Journal of Molecular Sciences ◽

10.3390/ijms19123702 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3702 ◽

Cited By ~ 12

Author(s):

Grazia Femminella ◽

Tony Thayanandan ◽

Valeria Calsolaro ◽

Klara Komici ◽

Giuseppe Rengo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Multimodal Imaging ◽

Molecular Mechanisms ◽

Imaging Techniques ◽

Structural Mri ◽

Imaging Biomarkers ◽

Significant Burden ◽

Made In

Alzheimer’s disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer’s, as they provide an in vivo window to the pathological processes occurring in Alzheimer’s brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer’s disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer’s research and clinical practice.

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Microglia in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200212155234 ◽

2020 ◽

Vol 17 (1) ◽

pp. 29-43 ◽

Cited By ~ 3

Author(s):

Patrick Süß ◽

Johannes C.M. Schlachetzki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Imaging Techniques ◽

Amyloid Β ◽

Disease Stage ◽

Disease Modifying Therapy ◽

Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

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Astrocytes and Adenosine A2A Receptors: Active Players in Alzheimer’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.666710 ◽

2021 ◽

Vol 15 ◽

Author(s):

Cátia R. Lopes ◽

Rodrigo A. Cunha ◽

Paula Agostinho

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

The Elderly ◽

Synaptic Function ◽

Morphological Alterations ◽

Functional Changes ◽

A2a Receptors ◽

Novel Therapeutic Strategies

Astrocytes, through their numerous processes, establish a bidirectional communication with neurons that is crucial to regulate synaptic plasticity, the purported neurophysiological basis of memory. This evidence contributed to change the classic “neurocentric” view of Alzheimer’s disease (AD), being astrocytes increasingly considered a key player in this neurodegenerative disease. AD, the most common form of dementia in the elderly, is characterized by a deterioration of memory and of other cognitive functions. Although, early cognitive deficits have been associated with synaptic loss and dysfunction caused by amyloid-β peptides (Aβ), accumulating evidences support a role of astrocytes in AD. Astrocyte atrophy and reactivity occurring at early and later stages of AD, respectively, involve morphological alterations that translate into functional changes. However, the main signals responsible for astrocytic alterations in AD and their impact on synaptic function remain to be defined. One possible candidate is adenosine, which can be formed upon extracellular catabolism of ATP released by astrocytes. Adenosine can act as a homeostatic modulator and also as a neuromodulator at the synaptic level, through the activation of adenosine receptors, mainly of A1R and A2AR subtypes. These receptors are also present in astrocytes, being particularly relevant in pathological conditions, to control the morphofunctional responses of astrocytes. Here, we will focus on the role of A2AR, since they are particularly associated with neurodegeneration and also with memory processes. Furthermore, A2AR levels are increased in the AD brain, namely in astrocytes where they can control key astrocytic functions. Thus, unveiling the role of A2AR in astrocytes function might shed light on novel therapeutic strategies for AD.

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Neuroprotective Role of Diosgenin, A NGF Stimulator, Against Aβ (1–42) Induced Neurotoxicity in Animal Model of Alzheimer’s Disease

10.21203/rs.3.rs-340454/v1 ◽

2021 ◽

Author(s):

Swati Som ◽

Justin Antony ◽

Palanisamy Dhanabal ◽

Ponnusankar Sivasankaran

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Spatial Learning ◽

Molecular Mechanisms ◽

Protective Action ◽

Amyloid Β ◽

Spatial Learning And Memory ◽

Avoidance Task ◽

Model Of Alzheimer’S Disease

Abstract Diosgenin is a neurosteroid derived from the plants and has been previously reported for its numerous health beneficial properties, such as anti-arrhythmic, hypolipidemic, and antiproliferative effects. Although several studies conducted earlier suggested cognition enhancement actions of diosgenin against neurodegenerative disorders, but the molecular mechanisms underlying are not clearly understood. In the present study, we investigated the neuroprotective effect of diosgenin in the wistar rats that received an intracerebroventricular injection of Amyloid-β (1–42) peptides, representing a rodent model of Alzheimer’s disease (AD). Animals were treated with 100 and 200 mg/kg/p.o of diosgenin for 28 days, followed by Amyloid-β (1–42) peptides infusion. Animals were assessed for the spatial learning and memory by using radial arm maze and passive avoidance task. Subsequently, animals were euthanized and brains were collected for biochemical estimations and histopathological studies. Our results revealed that, diosgenin administration dose dependently improved the spatial learning and memory and protected the animals from Amyloid-β (1–42) peptides induced disrupted cognitive functions. Further, biochemical analysis showed that diosgenin successfully attenuated Amyloid-β (1–42) mediated plaque load, oxidative stress, neuroinflammation and elevated acetylcholinesterase activity. In addition, histopathological evaluation also supported neuroprotective effects of diosgenin in hippocampus of rat brain when assessed using hematoxylin-eosin and Cresyl Violet staining. Thus, the aforementioned effects suggested protective action of diosgenin against Aβ (1–42) induced neuronal damage and thereby can serve as a potential therapeutic candidate for AD.

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Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

Biochemical Society Transactions ◽

10.1042/bst0390819 ◽

2011 ◽

Vol 39 (3) ◽

pp. 819-822 ◽

Cited By ~ 18

Author(s):

Ana M. Mata ◽

María Berrocal ◽

M. Rosario Sepúlveda

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Plasma Membrane ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Senile Plaques ◽

Amyloid Β ◽

Inhibitory Effect ◽

Amyloid Β Peptide ◽

Aβ Amyloid

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Aβ (amyloid β-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Aβ neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Aβ. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Aβ, which is consistent with the lack of any Aβ effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Aβ-mediated inhibition on PMCA.

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Perspectives in Molecular Imaging Using Staging Biomarkers and Immunotherapies in Alzheimer’s Disease

The Scientific World JOURNAL ◽

10.1155/2013/589308 ◽

2013 ◽

Vol 2013 ◽

pp. 1-16 ◽

Cited By ~ 5

Author(s):

Benoît Leclerc ◽

Abedelnasser Abulrob

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Beta Amyloid ◽

The Elderly ◽

Pittsburgh Compound B ◽

Diagnostic Strategies ◽

Positron Emission ◽

The Difference ◽

Near Future

Sporadic Alzheimer’s disease (AD) is an emerging chronic illness characterized by a progressive pleiotropic pathophysiological mode of actions triggered during the senescence process and affecting the elderly worldwide. The complex molecular mechanisms of AD not only are supported by cholinergic, beta-amyloid, and tau theories but also have a genetic basis that accounts for the difference in symptomatology processes activation among human population which will evolve into divergent neuropathological features underlying cognitive and behaviour alterations. Distinct immune system tolerance could also influence divergent responses among AD patients treated by immunotherapy. The complexity in nature increases when taken together the genetic/immune tolerance with the patient’s brain reserve and with neuropathological evolution from early till advance AD clinical stages. The most promising diagnostic strategies in today’s world would consist in performing high diagnostic accuracy of combined modality imaging technologies using beta-amyloid 42 peptide-cerebrospinal fluid (CSF) positron emission tomography (PET), Pittsburgh compound B-PET, fluorodeoxyglucose-PET, total and phosphorylated tau-CSF, and volumetric magnetic resonance imaging hippocampus biomarkers for criteria evaluation and validation. Early diagnosis is the challenge task that needs to look first at plausible mechanisms of actions behind therapies, and combining them would allow for the development of efficient AD treatment in a near future.

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Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

Antioxidants ◽

10.3390/antiox10091353 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1353

Author(s):

Francesca Romana Buccellato ◽

Marianna D’Anca ◽

Chiara Fenoglio ◽

Elio Scarpini ◽

Daniela Galimberti

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Oxidative Damage ◽

Molecular Mechanisms ◽

Biomarker Discovery ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Antioxidant Defenses ◽

Ageing Population

Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

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Hyperactivity Induced by Soluble Amyloid-β Oligomers in the Early Stages of Alzheimer's Disease

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.600084 ◽

2021 ◽

Vol 13 ◽

Author(s):

Audrey Hector ◽

Jonathan Brouillette

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Clinical Symptoms ◽

Epileptiform Activity ◽

Amyloid Β ◽

Gamma Oscillations ◽

Synaptic Activity ◽

Early Stages ◽

The Impact

Soluble amyloid-beta oligomers (Aβo) start to accumulate in the human brain one to two decades before any clinical symptoms of Alzheimer's disease (AD) and are implicated in synapse loss, one of the best predictors of memory decline that characterize the illness. Cognitive impairment in AD was traditionally thought to result from a reduction in synaptic activity which ultimately induces neurodegeneration. More recent evidence indicates that in the early stages of AD synaptic failure is, at least partly, induced by neuronal hyperactivity rather than hypoactivity. Here, we review the growing body of evidence supporting the implication of soluble Aβo on the induction of neuronal hyperactivity in AD animal models, in vitro, and in humans. We then discuss the impact of Aβo-induced hyperactivity on memory performance, cell death, epileptiform activity, gamma oscillations, and slow wave activity. We provide an overview of the cellular and molecular mechanisms that are emerging to explain how Aβo induce neuronal hyperactivity. We conclude by providing an outlook on the impact of hyperactivity for the development of disease-modifying interventions at the onset of AD.

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New pharmacological strategies for the treatment of alzheimer’s disease

10.5327/1516-3180.097 ◽

2021 ◽

Author(s):

Letícia Freitas de Castro Silva ◽

Elisa Pinheiro Weber ◽

Gleice Silva Toledo ◽

Josiane Fonseca Almeida

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Tau Protein ◽

Amyloid Β ◽

The Elderly ◽

New Drugs ◽

Pathophysiological Mechanisms ◽

Apoe Protein ◽

New Biomarkers

Introduction: Alzheimer’s disease (AD) is seen as the most important dementia, prevalent in the elderly over 60 years old. There is still no cure, and the pharmacological strategies are to delay the symptoms and development of the pathology. The pathophysiological mechanisms are: hyperphosphorylation of the tau protein and aggregation of amyloid-β. Update studies of the tested therapies target the main pathological mechanisms: accumulation of β amyloid (inhibitors and modulators of β-secretase and γ-secretase and active and passive anti-Aβ immunotherapies), tau protein (inhibition of abnormal hyperphosphorylation with GSK-3 inhibitors, passive and active immunotherapies and the use of intrathecal antisense oligonucleotides (ASOs) and correction of the ApoE protein (increase lipidation, correct structure, clearance of non-lipid ApoE and reduction of ApoE expression). Objectives and methodology: To develop a bibliographic review in order to address new drugs in the treatment of Alzheimer’s. Qualitative and descriptive study carried out by literary review with research on PubMed. Results: Several drugs have been tested in clinical trials, however, due to lack of effectiveness, none have been approved. Therefore, it’s important to understand the limitations of the tests developed as flaws in the methodology, insufficient understanding of the mechanisms involved and inclusion of patients in different stages of AD, so that future investigations can overcome these gaps. Conclusion: It’s important to investigate new pathophysiological mechanisms, as well as the factors that trigger AD. Diagnosis is essential, with further studies to identify new biomarkers of the disease that will also have an impact on the conduct of clinical trials.

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c-Jun N-Terminal Kinases in Alzheimer’s Disease: A Possible Target for the Modulation of the Earliest Alterations

Journal of Alzheimer s Disease ◽

10.3233/jad-201053 ◽

2020 ◽

pp. 1-13

Author(s):

Oriol Busquets ◽

Antoni Parcerisas ◽

Ester Verdaguer ◽

Miren Ettcheto ◽

Antoni Camins ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Amyloid Β ◽

Cellular Functions ◽

Synaptic Loss ◽

Master Regulators ◽

Cellular Processes ◽

Cholinergic Synapses ◽

Neuronal Transport

Given the highly multifactorial origin of Alzheimer’s disease (AD) neuropathology, disentangling and orderly knowing mechanisms involved in sporadic onset are arduous. Nevertheless, when the elements involved are dissected into smaller pieces, the task becomes more accessible. This review aimed to describe the link between c-Jun N-terminal Kinases (JNKs), master regulators of many cellular functions, and the early alterations of AD: synaptic loss and dysregulation of neuronal transport. Both processes have a role in the posterior cognitive decline observed in AD. The manuscript focuses on the molecular mechanisms of glutamatergic, GABA, and cholinergic synapses altered by the presence of amyloid-β aggregates and hyperphosphorylated tau, as well as on several consequences of the disruption of cellular processes linked to neuronal transport that is controlled by the JNK-JIP (c-jun NH2-terminal kinase (JNK)–interacting proteins (JIPs) complex, including the transport of AβPP or autophagosomes.

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