Endocannabinoid metabolism and Alzheimer’s disease

Alzheimer’s disease(AD)is the most common cause of dementia in the elderly.Unfortunately,there are no effective therapies currently available for prevention and treatment of AD.As it is clear now,the etiology of AD is multifactorial and complex.This means that development of AD is linked to multiple mechanisms or signaling pathways and that a single-target therapy for AD is likely insufficient to achieve therapeutic goals.Therefore,an ideal therapy for AD should be able to modify the disease through multiple signaling pathways.2-Arachidonoylglycerol(2-AG)is an endogenous cannabinoid(endocannabinoid)displayinganti-inflammator y a n d neuroprotective properties,while its metabolites are arachidonic acid(AA)and AA-derived prostaglandins and leukotrienes,which are proinflammatory and neurotoxic(Figure 1).     

Clinical features of Alzheimer’s disease

The preclinical stage of Alzheimer’s disease is inconspicuous and there are – almost by definition – no reliable and valid symptoms and signs which would allow a very early diagnosis before the manifestation of irreversible deficits. For a clinical diagnosis of dementia, cognitive impairment has to be severe enough to compromise the activities of daily living. In the mild dementia stage, difficulties with declarative memory are usually prominent; depressive symptoms are not infrequent, but the patient usually manages to live alone. Supervision is needed in the moderate dementia stage, when other cognitive domains are affected in a more obvious manner and non-cognitive disturbances of thought, perception, affect, and behavior put increasing stress on the caregivers. Complete dependence of the patients, who frequently develop neurological disturbances, is typical of the late stage of illness. The life expectancy of patients with a clinical diagnosis of Alzheimer’s disease is significantly reduced, but to date there is hope that the period of relative well-being and not of suffering can be prolonged with modern symptomatic treatment interventions.     

Diagnostic and therapeutic potential of exosomal miRNAs in Alzheimer’s disease

Alzheimer’s disease(AD)is a primary cause of dementia.AD is a neurodegenerative disorder,characterized by synapses loss,extracellular amyloid plaques composed of the amyloid-βpeptide(Aβ)and intracellular aggregates of hyperphosphorylated tau protein.AD is a complex disease linked to multiple interacting factors,both environmental and genetic,which can contribute to the onset and severity of the disease.Longitudinal studies have highlighted several cardiovascular risk factors that can increase the risk of AD.The genetic landscape of AD has changed dramatically in recent decades.Early studies identified mutations in the amyloid precursor protein gene(APP)as well as proteins that are involved in the enzymatic cleavage of APP to toxicβ-amyloid(Aβ),namely presenilin-1 and presnilin-2.However,these mutations were found in familial cases of early-onset AD,while the causes of sporadic late-onset AD are still unknown.The latest advances in Genomewide Association Studies(GWAS),sequencing,and bioinformatics have begun to unravel the complex genetic architecture of the sporadic form of AD.GWAS were able to uncover common variants with high frequency in the population that individually carried low risk(Robinson et al.,2017).The advent of next-generation and thirdgeneration sequencing platforms shows great promise in further unravelling the genetics of AD.     

Evaluation of suprachiasmatic nucleus in Alzheimer’s disease with non-invasive magnetic resonance methods

The suprachiasmatic nucleus and Alzheimer’s disease(AD):AD is the most frequently diagnosed form of dementia,with the total number of AD patients worldwide expected to triple by 2050 compared to 2015(Prince et al.,2015).Despite years of research,much of the AD pathology remains unclear with no treatment or cure available.Besides its two hallmarks,amyloid-β(Aβ)plagues and hyperphosphorylated tau tangles,a distortion of circadian rhythms is commonly observed.Furthermore,poor sleep quality or trouble falling asleep are common AD symptoms,sometimes developing 10-15 years before cognitive symptoms associated with AD(Ju et al.,2014).     

Recent advancements toward non-invasive imaging of retinal amyloid-beta for early detection of Alzheimer’s disease

Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by progressive cognitive impairment suggested to be induced by the accumulation of amyloid-β(Aβ)in the brain,especially in the hippocampus.Cerebral Aβdeposits may be detected through positron emission tomography(PET)as early as two decades before clinically diagnosed AD-associated dementia,which provides the opportunity for early therapeutic interventions(Wang and Mao,2021).PET may not be suitable for AD screening since it is invasive,costly,and inaccessible for routine clinical use or population screening.Aβdeposits have also been identified throughout the retina,which is a developmental outgrowth of the diencephalon and shares physiological and pathological pathways with the central nervous system(London et al.,2013).Patients with mild cognitive impairment and early AD are reported to have visual disturbances involving visual field loss with reported thinning of the retinal layers including the retinal nerve fiber layer,ganglion cell layer,and inner plexiform layer(Koronyo-Hamaoui et al.,2011;Wang and Mao,2021).Retinal Aβdeposits have been detected prior to the manifestation of cerebral Aβdeposits in transgenic mice models of AD(Koronyo-Hamaoui et al.,2011;Habiba et al.,2021).Since the retina provides an easily accessible location for non-invasive imaging,retinal Aβmay have the potential to be a surrogate for cerebral Aβand a biomarker for the detection of AD prior to irreversible cognitive impairment.     

Estrogens still represent an attractive therapeutic approach for Alzheimer’s disease

Alzheimer’s disease(AD)is a progressive neurodegenerative condition that goes f rom mild cogni t ive impai rment in prodromal disease to severely disabling deficits in advanced stages.The risk for AD development,as well as progression and severity,clearly differ between men and women(Pike,2017).Epidemiological studies have shown that there is a significantly increased prevalence in the development of AD in women compared to men,which is usually explained by the longer lifespan of women.This increased frequency may be due to the interplay between age and sex,in which genetic factors together with hormonal and metabolic patterns play a crucial role.Moreover,cognitive impairment has been confirmed to be greater in women than in men at the same stage of AD,likely due to reduced estrogen levels in postmenopausal women(Laws et al.,2016).     

Biomarker-guided drug therapy: personalized medicine for treating Alzheimer’s disease

Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyloid-beta(Aβ)plaques and neurofibril tangles.Currently,there are no disease-modifying treatments available for AD,except for a couple of the US Food and Drug Administration(FDA)-approved drugs to improve cognitive function by blocking N-methyl-D-aspartate receptors or cholinesterase activity(Panza et al.,2019).     

The blood-brain barrier models to study apolipoprotein E genotypes in Alzheimer’s disease

Alzheimer’s disease(AD)is a neurodegenerative disease that is characterized by an age-dependent progressive decline of memory,impairment of cognitive functions and changes in personality and behavior.Despite the improvement in understanding of the mechanisms underlying the disease,AD remains an incurable complex disorder with multifaceted pathophysiology to date.Apolipoprotein E(ApoE)is the main cholesterol carrier in the brain that supports lipid transport between brain cells.The individuals carrying the APOE4 allele are known to be at increased risk of developing AD compared with those carrying the more common APOE3 allele.     

Early Intervention in Alzheimer’s Disease: How Early is Early Enough?

In 1906,Dr.Alois Alzheimer reported a case of dementia and thought it was a new type of disease.Later,Dr.Emil Kraepelin named it Alzheimer’s disease(AD).One hundred years later,AD has become the most common type of dementia affecting the elderly population and a heavy health burden.However,the pathogenesis of the disease remains unclear,and no disease-modifying therapies are available to prevent,halt,or even slow the progression of the disease[1].     

How would preclinical Alzheimer’s disease (AD pathology) occur? An insight from a genomic instability mouse model

More than 95%of Alzheimer’s disease(AD)is late-onset,in which patients show clinical cognition/behavior symptoms after age 65.Unlike early-onset AD that comes with mutations in genes directly involved in amyloid metabolism(APP,PSEN),genetic predispositions associated with late-onset AD are harder to pinpoint,and their mechanistic links to AD development need further investigation.Although the development mechanism of late-onset AD remains controversial,amyloid-beta accumulation,initiated in middle age,is widely accepted as the triggering event for early AD pathology(Du Bois et al.,2010;Sterling et al.,2011).     

Sleep Disturbance: An Early Sign of Alzheimer’s Disease

Alzheimer's disease(AD)is a progressive neurodegenerative disorder associated with cognitive impairment in older adults.The accumulation of insoluble forms of amyloid-β(Aβ)in plaques in extracellular spaces and the aggregation of hyperphosphorylated microtubule-associated protein tau in neurofibrillary tangles in neurons are considered to be central pathological features of A D[1,2].     

Pathological features of cerebral cortical capillaries are doubled in Alzheimer’s disease and Parkinson’s disease

Cerebral capillaries represent a major interface between the general circulation and the central nervous system and are responsible for sufficient and selective nutrient transport to the brain. Structural damage or dysfunctioning carrier systems of such an active barrier leads to compromised nutrient trafficking. Subsequently, a decreased nutrient availability in the neural tissue may contribute to hampered neuronal metabolism, hence to behavioral and cognitive functional deficiencies. Here we focus on the ultrastrucutral abnormalities of cerebral microvessels in Alzheimer’s disease (AD; n = 5) and Parkinson’s diseasse (PD; n = 10). The capillary microanatomy in samples from the cingulate cortex was investigated by electron microscopy and severe damage to the vessel walls was observed. Characteristic pathological changes including capillary basement membrane thickening and collagen accumulation in the basement membrane were enhanced in both AD and PD. The incidence of capillaries with basement membrane deposits was two times higher in AD and PD than in age-matched controls. Degenerative pericytes in all groups appeared at a similar frequency. The data indicate that basement membrane deposists, as opposed to pericytic degeneration, represent an important pathological feature of AD and PD and suggest that capillary dysfunction may play a causal role in the development of these two major neurodegenerative diseases. Received: 21 July 1999 / Revised, accepted: 21 December 1999     

Alzheimer’s disease

Psychiatric Quarterly - It would appear, on the basis of this study, that Alzheimer’s disease is a distinct clinicopathologic entity which, while not common, is not so rare as commonly...     

Alzheimer’s disease

Conclusions It would appear, on the basis of this study, that Alzheimer's disease is a distinct clinicopathologic entity which, while not common, is not so rare as commonly believed.Finally, it is pertinent to emphasize that familiarity with the clinical picture will show that many more cases exist than have hitherto been suspected.     

Globodera pallida,a non-transgenic invertebrate as a new model for investigating Alzheimer’s disease(and other proteinopathies)?

Biological models of Alzheimer’s disease(AD):Non-human models have contributed tremendously to the understanding of AD and its underlying pathological processes.These models have aided the investigation of the genetic and environmental risk factors.They also have enabled the progression of candidate therapies into human clinical trials.Because of similarities with human brain anatomy and genetics,rodent models have been used extensively to recapitulate some aspects of AD pathology,measure AD-associated behavioral parameters and related nervous system dysfunctions(Eriksen and Janus,2007).For instance,transgenic mice overexpressing human amyloid precursor protein have furthered the development of the amyloid cascade hypothesis as a central pillar of familial AD.     

The genetics of Alzheimer’s disease

Alzheimer’s disease (AD) is a genetically complex disorder. Mutations in the amyloid precursor protein and presenilin 1 (PS1) genes are fully penetrant and cause early-onset AD. Mutations in presenilin 2, a PS1 homologue, cause partially penetrant autosomal dominant AD with onset age beginning at 40 years and extending past 75 years. A fourth gene, apolipoprotein E (ApoE) is a riskfactor for late-onset AD. Over 40 genes have been tested as AD candidate genes, yet none has been clearly established as an AD risk factor. Linkage studies have implicated a number of chromosome regions as possible sites for late-onset AD loci with the strongest evidence being for chromosome 12. Candidate genes in this regioninclude α2-macroglobulin (A2M) and low-density lipoprotein receptor-related gene (LRP), although neither has been clearly established as an AD gene. Identification of additional late-onset genes will require larger samples, more sophisticated analysis methods, and large-scale positional cloning efforts.     

Molecular genetics of Alzheimer’s disease

Alzheimer disease (AD) is the most common cause of dementia. In the past decade, many advances in the understanding of the etiology of AD have been reported. Familial early onset AD is a heterogeneous disorder that can be caused by mutations in at least three different genes. Current studies are focused on identifying genetic risk factors for late onset AD. In this article, the authors will review the progress in understanding the pathogenic implications of the genes mutated in familial early onset AD and the mapping studies to identify additional genes involved in late-onset AD.