On the reconceptualization of Alzheimer’s disease

In the hope of future treatments to prevent or slow down the disease, there is a strong movement towards an ever‐earlier detection of Alzheimer’s disease (AD). In conjunction with scientific developments, this has prompted a reconceptualization of AD, as a slowly progressive pathological process with a long asymptomatic phase. New concepts such as ‘preclinical’ and ‘prodromal’ AD have been introduced, raising a number of conceptual and ethical questions. We evaluate whether these new concepts are theoretically defensible, in light of theories of health and disease, and whether they should be understood as disease or as an at‐risk state. We introduce a pragmatic view on disease concepts and argue that an evaluation of the reconceptualization of AD should also take its aims and effects into account, and assess their ethical acceptability. The reconceptualization of AD is useful to coordinate research into preventive strategies, and may potentially benefit future patients. However, in the short term, early detection and labelling of ‘preclinical AD’ can potentially harm people. Since there is no treatment available and the predictive value is unclear, it may only create a group of ‘patients‐in‐waiting’ who may suffer from anxiety, uncertainty and stigmatization, but will never actually develop dementia. We conclude that only if the promise of preventive medication materializes, will the reconceptualization of AD turn out unequivocally to be for the better. Otherwise, the reconceptualization may do more harm than good.     

Gene therapy in Alzheimer’s disease – potential for disease modification

• ? Introduction
• ? Targets and ongoing research
  • ‐ NGF
    • ‐ Neurotrophic function of NGF
    • ‐ Levels of NGF in AD
    • ‐ Role of NGF in AD
    • ‐ NGF as a therapeutic agent
    • ‐ Development of NGF gene therapy
    • ‐ In vivo gene delivery of NGF
  • ‐ BDNF
    • ‐ Neurotrophic function of BDNF
    • ‐ BDNF levels in AD
    • ‐ BDNF function in AD
    • ? Towards BDNF gene therapy
  • ‐ Neprilysin
    • ‐ Role of neprilysin in AD
    • ‐ Neprilysin levels in AD
    • ‐ Gene delivery of neprilysin in AD animal models
• ? Potential gene therapy target candidates
  • ‐ APOE
  • ‐ ECE
  • ‐ Cathepsin B
  • ‐ Other Aβ degrading enzymes
• ? Down‐regulation of AD‐associated proteins by siRNA
  • ‐ BACE1
  • ‐ APP
• ? Concluding remarks

Alzheimer’s disease (AD) is the major cause of dementia in the elderly, leading to memory loss and cognitive decline. The mechanism underlying onset of the disease has not been fully elucidated. However, characteristic pathological manifestations include extracellular accumulation and aggregation of the amyloid β‐peptide (Aβ) into plaques and intracellular accumulation and aggregation of hyperphosphorylated tau, forming neurofibrillary tangles. Despite extensive research worldwide, no disease modifying treatment is yet available. In this review, we focus on gene therapy as a potential treatment for AD, and summarize recent work in the field, ranging from proof‐of‐concept studies in animal models to clinical trials. The multifactorial causes of AD offer a variety of possible targets for gene therapy, including two neurotrophic growth factors, nerve growth factor and brain‐derived neurotrophic factor, Aβ‐degrading enzymes, such as neprilysin, endothelin‐converting enzyme and cathepsin B, and AD associated apolipoprotein E. This review also discusses advantages and drawbacks of various rapidly developing virus‐mediated gene delivery techniques for gene therapy. Finally, approaches aiming at down‐regulating amyloid precursor protein (APP) and β‐site APP cleaving enzyme 1 levels by means of siRNA‐mediated knockdown are briefly summarized. Overall, the prospects appear hopeful that gene therapy has the potential to be a disease modifying treatment for AD.     

Docosahexaenoic acid disrupts in vitro amyloid β1‐40 fibrillation and concomitantly inhibits amyloid levels in cerebral cortex of Alzheimer’s disease model rats

We have previously reported that dietary docosahexaenoic acid (DHA) improves and/or protects against impairment of cognition ability in amyloid beta_1‐40 (Aβ_1‐40)‐infused Alzheimer’s disease (AD)‐model rats. Here, after the administration of DHA to AD model rats for 12 weeks, the levels of Aβ_1‐40, cholesterol and the composition of fatty acids were investigated in the Triton X100‐insoluble membrane fractions of their cerebral cortex. The effects of DHA on the in vitro formation and kinetics of fibrillation of Aβ_1‐40 were also investigated by thioflavin T fluorescence spectroscopy, transmission electron microscopy and fluorescence microscopy. Dietary DHA significantly decreased the levels of Aβ_1‐40, cholesterol and saturated fatty acids in the detergent insoluble membrane fractions of AD rats. The formation of Aβ fibrils was also attenuated by their incubation with DHA, as demonstrated by the decreased intensity of thioflavin T‐derived fluorescence and by electron micrography. DHA treatment also decreased the intensity of thioflavin fluorescence in preformed‐fibril Aβ peptides, demonstrating the anti‐amyloidogenic effects of DHA. We then investigated the effects of DHA on the levels of oligomeric amyloid that is generated during its in vitro transformation from monomers to fibrils, by an anti‐oligomer‐specific antibody and non‐reducing Tris‐Glycine gradient (4–20%) gel electrophoresis. DHA concentration‐dependently reduced the levels of oligomeric amyloid species, suggesting that dietary DHA‐induced suppression of in vivo Aβ_1‐40 aggregation occurs through the inhibitory effect of DHA on oligomeric amyloid species.     

Nurr1 (NR4A2) regulates Alzheimer’s disease‐related pathogenesis and cognitive function in the 5XFAD mouse model

The orphan nuclear receptor Nurr1 (also known as NR4A2) is critical for the development and maintenance of midbrain dopaminergic neurons, and is associated with Parkinson's disease. However, an association between Nurr1 and Alzheimer's disease (AD)‐related pathology has not previously been reported. Here, we provide evidence that Nurr1 is expressed in a neuron‐specific manner in AD‐related brain regions; specifically, it is selectively expressed in glutamatergic neurons in the subiculum and the cortex of both normal and AD brains. Based on Nurr1’s expression patterns, we investigated potential functional roles of Nurr1 in AD pathology. Nurr1 expression was examined in the hippocampus and cortex of AD mouse model and postmortem human AD subjects. In addition, we performed both gain‐of‐function and loss‐of‐function studies of Nurr1 and its pharmacological activation in 5XFAD mice. We found that knockdown of Nurr1 significantly aggravated AD pathology while its overexpression alleviated it, including effects on Aβ accumulation, neuroinflammation, and neurodegeneration. Importantly, 5XFAD mice treated with amodiaquine, a highly selective synthetic Nurr1 agonist, showed robust reduction in typical AD features including deposition of Aβ plaques, neuronal loss, microgliosis, and impairment of adult hippocampal neurogenesis, leading to significant improvement of cognitive impairment. These in vivo and in vitro findings suggest that Nurr1 critically regulates AD‐related pathophysiology and identify Nurr1 as a novel AD therapeutic target.     

Neuroprotective effects of hydrogen sulfide on Parkinson’s disease rat models

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN). The present study was designed to examine the therapeutic effect of hydrogen sulfide (H₂S, a novel biological gas) on PD. The endogenous H₂S level was markedly reduced in the SN in a 6‐hydroxydopamine (6‐OHDA)‐induced PD rat model. Systemic administration of NaHS (an H₂S donor) dramatically reversed the progression of movement dysfunction, loss of tyrosine‐hydroxylase positive neurons in the SN and the elevated malondialdehyde level in injured striatum in the 6‐OHDA‐induced PD model. H₂S specifically inhibited 6‐OHDA evoked NADPH oxidase activation and oxygen consumption. Similarly, administration of NaHS also prevented the development of PD induced by rotenone. NaHS treatment inhibited microglial activation in the SN and accumulation of pro‐inflammatory factors (e.g. TNF‐α and nitric oxide) in the striatum via NF‐κB pathway. Moreover, significantly less neurotoxicity was found in neurons treated with the conditioned medium from microglia incubated with both NaHS and rotenone compared to that with rotenone only, suggesting that the therapeutic effect of NaHS was, at least partially, secondary to its suppression of microglial activation. In summary, we demonstrate for the first time that H₂S may serve as a neuroprotectant to treat and prevent neurotoxin‐induced neurodegeneration via multiple mechanisms including anti‐oxidative stress, anti‐inflammation and metabolic inhibition and therefore has potential therapeutic value for treatment of PD.     

SCFFbx2‐E3‐ligase‐mediated degradation of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function

BACE1 (β‐secretase) plays a central role in the β‐amyloidogenesis of Alzheimer’s disease (AD). The ubiquitin–proteasome system, a major intracellular protein quality control system, has been implicated recently in BACE1 metabolism. We report that the SCF^Fbx2‐E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F‐box‐associated domain. Physiologically, we found that Fbx2 was expressed in various intracellular organelles in brain neurons and that BACE1 is colocalized with Fbx2 and the amyloid precursor protein (APP), mainly at the early endosome and endoplasmic reticulum. The former are believed to be the major intracellular compartments where the APP is cleaved by BACE1 and β‐amyloid is produced. Importantly, we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β‐amyloid production. In the search for specific endogenous modulators of Fbx2 expression, we found that PPARγ coactivator‐1α (PGC‐1α) was capable of promoting the degradation of BACE1 through a mechanism involving Fbx2 gene expression. Interestingly, we found that the expression of both Fbx2 and PGC‐1α was significantly decreased in the brains of aging Tg2576 mice. Our in vivo studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and activity, coincidentally reducing β‐amyloid levels and rescuing synaptic deficits. Our study is the first to suggest that promoting Fbx2 in the brain may represent a novel strategy for the treatment of AD.     

Endometrial stem cell transplantation restores dopamine production in a Parkinson’s disease model

Parkinson’s disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons. Adult human endometrial derived stem cells (HEDSC), a readily obtainable type of mesenchymal stem‐like cell, were used to generate dopaminergic cells and for transplantation. Cells expressing CD90, platelet derived growth factor (PDGF)‐Rβ and CD146 but not CD45 or CD31 were differentiated in vitro into dopaminergic neurons that exhibited axon projections, pyramidal cell bodies and dendritic projections that recapitulate synapse formation; these cells also expressed the neural marker nestin and tyrosine hydroxylase, the rate‐limiting enzyme in dopamine synthesis. Whole cell patch clamp recording identified G‐protein coupled inwardly rectifying potassium current 2 channels characteristic of central neurons. A 1‐methyl 4‐phenyl 1,2,3,6‐tetrahydro pyridine induced animal model of PD was used to demonstrate the ability of labelled HEDSC to engraft, migrate to the site of lesion, differentiate in vivo and significantly increase striatal dopamine and dopamine metabolite concentrations. HEDSC are a highly inducible source of allogenic stem cells that rescue dopamine concentrations in an immunocompetent PD mouse model.     

The potential benefits of dental implants on the oral health quality of life of people with Parkinson’s disease

Objective: To investigate how dental implants impact on the oral health quality of life of people with Parkinson’s disease (PD). Background: PD is a progressive neurological disorder that can result in a number of oral health care challenges, including denture difficulties. Lack of evidence related to use of implants in PD prompted this study to investigate their use in this group of people. Materials and methods: Nine people with PD were provided with either fixed or removable prostheses using Astra‐Tech implants. Participants completed the socio‐dental questionnaire, ‘The Dental Impact on Daily Living Assessment’ (DIDL) prior to implant surgery, and at 3 and 12 months after provision of the final prosthesis. DIDL comprises two components – the Oral Health Quality of Life Inventory (OH‐QoL) and the Self‐Reported Assessment of Oral Health and Functional Status (SROH). Results: Nine people (with an age range of 54–77 years) had implants placed. The implant success rate was 85 and 81% in the maxilla and mandible, respectively. The OH‐QoL and SROH results (analysed using the one‐way analysis of variance and pairwise multiple comparisons) demonstrated a significant improvement in the domains of eating and satisfaction with the prosthesis after 3 months, which was maintained at the twelve month review. The OH‐QoL indicated a gradual improvement in oral well‐being over the 12‐month period. Conclusion: The oral health quality of life of people with PD was improved by the use of dental implants, indicating this as a viable treatment option.     

Concept of functional imaging of memory decline in Alzheimer’s disease

Functional imaging methods such as Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) have contributed inestimably to the understanding of physiological cognitive processes in the brain in the recent decades. These techniques for the first time allowed the in vivo assessment of different features of brain function in the living human subject. It was therefore obvious to apply these methods to evaluate pathomechanisms of cognitive dysfunction in disorders such as Alzheimer’s disease (AD) as well. One of the most dominant symptoms of AD is the impairment of memory. In this context, the term “memory” represents a simplification and summarizes a set of complex cognitive functions associated with encoding and retrieval of different types of information. A number of imaging studies assessed the functional changes of neuronal activity in the brain at rest and also during performance of cognitive work, with regard to specific characteristics of memory decline in AD. In the current article, basic principles of common functional imaging procedures will be explained and it will be discussed how they can be reasonably applied for the assessment of memory decline in AD. Furthermore, it will be illustrated how these imaging procedures have been employed to improve early and specific diagnosis of the disease, to understand specific pathomechanisms of memory dysfunction and associated compensatory mechanisms, and to draw reverse conclusions on physiological function of memory.     

Altered expression of claudin family proteins in Alzheimer’s disease and vascular dementia brains

Claudins (Cls) are a multigene family of transmembrane proteins with different tissue distribution, which have an essential role in the formation and sealing capacity of tight junctions (TJs). At the level of the blood–brain barrier (BBB), TJs are the main molecular structures which separate the neuronal milieu from the circulatory space, by a restriction of the paracellular flow of water, ions and larger molecules into the brain. Different studies suggested recently significant BBB alterations in both vascular and degenerative dementia types. In a previous study we found in Alzheimer’s disease (AD) and vascular dementia (VaD) brains an altered expression of occludin, a molecular partner of Cls in the TJs structure. Therefore in this study, using an immunohistochemical approach, we investigated the expression of Cl family proteins (Cl‐2, Cl‐5 and Cl‐11) in frontal cortex of aged control, AD and VaD brains. To estimate the number of Cl‐expressing cells, we applied a random systematic sampling and the unbiased optical fractionator method. We found selected neurons, astrocytes, oligodendrocytes and endothelial cells expressing Cl‐2, Cl‐5 and Cl‐11 at detectable levels in all cases studied. We report a significant increase in ratio of neurons expressing Cl‐2, Cl‐5 and Cl‐11 in both AD and VaD as compared to aged controls. The ratio of astrocytes expressing Cl‐2 and Cl‐11 was significantly higher in AD and VaD as compared to aged controls. The ratio of oligodendrocytes expressing Cl‐11 was significantly higher in AD and the ratio of oligodendrocytes expressing Cl‐2 was significantly higher in VaD as compared to aged controls. Within the cerebral cortex, Cls were selectively expressed by pyramidal neurons, which are the ones responsible for cognitive processes and affected by AD pathology. Our findings suggest a new function of Cl family proteins which might be linked to response to cellular stress.