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.     

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.     

Mutant presenilin‐1 deregulated peripheral immunity exacerbates Alzheimer‐like pathology

Mutations in the presenilin‐1 (PS1) gene are independent causes of familial Alzheimer's disease (AD). AD patients have dysregulated immunity, and PS1 mutant mice exhibit abnormal systemic immune responses. To test whether immune function abnormality caused by a mutant human PS1 gene (mhPS1) could modify AD‐like pathology, we reconstituted immune systems of AD model mice carrying a mutant human amyloid precursor protein gene (mhAPP; Tg2576 mice) or both mhAPP and mhPS1 genes (PSAPP mice) with allo‐geneic bone marrow cells. Here, we report a marked reduction in amyloid‐β (Aβ) levels, β‐amyloid plaques and brain inflammatory responses in PSAPP mice following strain‐matched wild‐type PS1 bone marrow reconstitution. These effects occurred with immune switching from pro‐inflammatory T helper (Th) 1 to anti‐inflammatory Th2 immune responses in the periphery and in the brain, which likely instructed microglia to phagocytose and clear Aβ in an ex vivo assay. Conversely, Tg2576 mice displayed accelerated AD‐like pathology when reconstituted with mhPS1 bone marrow. These data show that haematopoietic cells bearing the mhPS1 transgene exacerbate AD‐like pathology, suggesting a novel therapeutic strategy for AD based on targeting PS1 in peripheral immune cells.     

Synthesis and biological evaluation of thieno[3,2-c]pyrazol-3-amine derivatives as potent glycogen synthase kinase 3β inhibitors for Alzheimer’s disease

Glycogen synthase kinase 3β (GSK-3β) catalyses the hyperphosphorylation of tau protein in the Alzheimer’s disease (AD) pathology. A series of novel thieno[3,2-c]pyrazol-3-amine derivatives were designed and synthesised and evaluated as potential GSK-3β inhibitors by structure-guided drug rational design approach. The thieno[3,2-c]pyrazol-3-amine derivative 16b was identified as a potent GSK-3β inhibitor with an IC₅₀ of 3.1 nM in vitro and showed accepted kinase selectivity. In cell levels, 16b showed no toxicity on the viability of SH-SY5Y cells at the concentration up to 50 μM and targeted GSK-3β with the increased phosphorylated GSK-3β at Ser9. Western blot analysis indicated that 16b decreased the phosphorylated tau at Ser396 in a dose-dependent way. Moreover, 16b effectively increased expressions of β-catenin as well as the GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth. Therefore, the thieno[3,2-c]pyrazol-3-amine derivative 16b could serve as a promising GSK-3β inhibitor for the treatment of 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.     

Early defect of transforming growth factor β1 formation in Huntington’s disease

A defective expression or activity of neurotrophic factors, such as brain‐ and glial‐derived neurotrophic factors, contributes to neuronal damage in Huntington’s disease (HD). Here, we focused on transforming growth factor‐β (TGF‐β₁), a pleiotropic cytokine with an established role in mechanisms of neuroprotection. Asymptomatic HD patients showed a reduction in TGF‐β₁ levels in the peripheral blood, which was related to trinucleotide mutation length and glucose hypometabolism in the caudate nucleus. Immunohistochemical analysis in post‐mortem brain tissues showed that TGF‐β₁ was reduced in cortical neurons of asymptomatic and symptomatic HD patients. Both YAC128 and R6/2 HD mutant mice showed a reduced expression of TGF‐β₁ in the cerebral cortex, localized in neurons, but not in astrocytes. We examined the pharmacological regulation of TGF‐β₁ formation in asymptomatic R6/2 mice, where blood TGF‐β₁ levels were also reduced. In these R6/2 mice, both the mGlu2/3 metabotropic glutamate receptor agonist, LY379268, and riluzole failed to increase TGF‐β₁ formation in the cerebral cortex and corpus striatum, suggesting that a defect in the regulation of TGF‐β₁ production is associated with HD. Accordingly, reduced TGF‐β₁ mRNA and protein levels were found in cultured astrocytes transfected with mutated exon 1 of the human huntingtin gene, and in striatal knock‐in cell lines expressing full‐length huntingtin with an expanded glutamine repeat. Taken together, our data suggest that serum TGF‐β₁ levels are potential biomarkers of HD development during the asymptomatic phase of the disease, and raise the possibility that strategies aimed at rescuing TGF‐β₁ levels in the brain may influence the progression of HD.     

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.