Current Alzheimer Research - Volume 17, Issue 7, 2020

Background: Amyloid β (Aβ) peptide deposition is considered as the main cause of Alzheimer’s disease (AD). Previously, we have shown that a Zn containing neutral phthalocyanine (Zn-Pc) inhibits Aβ fibril formation. Objective: The objective of this study is to investigate the effects of a cationic gallium containing Pc (GaCl-Pc) on Aβ fibril formation process. Methods and Result: Aβ fibril formation was induced by incubating synthetic Aβ peptides in a fibril forming buffer, and the amount of fibril was evaluated by ThT fluorescence assay. GaCl-Pc dosedependently inhibited both Aβ1-40 and Aβ1-42 fibril formation. It mainly inhibited the elongation phase of Aβ1-42 fibril formation kinetics, but not the lag phase. Western blotting results showed that it did not inhibit its oligomerization process, rather increased it. Additionally, GaCl-Pc destabilized preformed Aβ1- 42 fibrils dose-dependently in vitro condition, and decreased Aβ levels in the brain slice culture of APP transgenic AD model mice (J20 strain). Near-infrared scanning results showed that GaCl-Pc had the ability to bind to Aβ1-42. MTT assay demonstrated that GaCl-Pc did not have toxicity towards a neuronal cell line (A1) in culture rather, showed protective effects on Aβ-induced toxicity. Moreover, it dosedependently decreased Aβ-induced reactive oxygen species levels in A1 culture. Conclusion: Thus, our result demonstrated that GaCl-Pc decreased Aβ aggregation and destabilized the preformed fibrils. Since cationic molecules show a better ability to cross the blood-brain barrier, cationic GaCl-Pc could be important for the therapy of AD.

Background: Neuronal Microtubule (MT) tau protein, providing cytoskeleton to neuronal cells, plays a vital role, including maintenance of cell shape, intracellular transport, and cell division. Tau hyperphosphorylation mediated MT destabilization results in axonopathy, additionally neurotransmitter deficit and ultimately causing Alzheimer's disease. Pre-clinically, streptozotocin (3mg/kg, 10μl/ unilateral, ICV) stereotaxically mimics the behavioral and neurochemical alterations similar to Alzheimer's tau pathology resulting in MT assembly defects further lead to neuropathological cascades. Objective: Clinically approved medications such as Donepezil (DNP), rivastigmine, and Memantine (MEM) are responsible for symptomatic care only, but there is no specific pharmacological intervention that directly interacts with the neuronal microtubule destabilization. Methods: The current study focused on the involvement of anti-cancer agent microtubule stabilizer cabazitaxel at a low dose (0.5 and 2 mg/kg) alone and in combination with standard drugs DNP (5 mg/kg), MEM (10 mg/kg) and microtubule stabilizer Epothilone D (EpoD) (3 mg/kg) in the prevention of intracerebroventricular streptozotocin (ICV-STZ) intoxicated microtubule-associated tau protein hyperphosphorylation. Results: Chronic treatment of CBZ at a low dose alone and in combination with standard drugs showing no side effect and significantly improve the cognitive impairment, neurochemical alterations along with reducing the level of hyperphosphorylated tau by preventing the breakdown of the neuronal cytoskeleton, respectively. Conclusion: The above findings suggested that CBZ at low dose show neuroprotective effects against ICV-STZ induced microtubule-associated tau protein hyperphosphorylation in rats and may be an effective agent for the preventive treatment of AD.

Background: Mitochondrial dysfunction is a pathological feature that manifests early in the brains of patients with Alzheimer’s Disease (AD). The disruption of mitochondrial dynamics contributes to mitochondrial morphological and functional impairments. Our previous study demonstrated that the expression of genes involved in amyloid beta generation was altered in the peripheral blood of AD patients. Objective: The aim of this study was to further investigate the relative levels of mitochondrial genes involved in mitochondrial dynamics, including mitochondrial fission and fusion, and mitophagy in peripheral blood samples from patients with AD compared to healthy controls. Methods: The mRNA levels were analyzed by real-time polymerase chain reaction. Gene expression profiles were assessed in relation to cognitive performance. Results: Significant changes were observed in the mRNA expression levels of fission-related genes; Fission1 (FIS1) levels in AD subjects were significantly higher than those in healthy controls, whereas Dynamin- related protein 1 (DRP1) expression was significantly lower in AD subjects. The levels of the mitophagy-related genes, PTEN-induced kinase 1 (PINK1) and microtubule-associated protein 1 light chain 3 (LC3), were significantly increased in AD subjects and elderly controls compared to healthy young controls. The mRNA levels of Parkin (PARK2) were significantly decreased in AD. Correlations were found between the expression levels of FIS1, DRP1 and PARK2 and cognitive performance scores. Conclusion: Alterations in mitochondrial dynamics in the blood may reflect impairments in mitochondrial functions in the central and peripheral tissues of AD patients. Mitochondrial fission, together with mitophagy gene profiles, might be potential considerations for the future development of blood-based biomarkers for AD.

Background and Objective: Hypoxic Preconditioning (HPC) has been well established to trigger endogenous mechanisms of neuroprotection basing on models of hypoxic and ischemic diseases in the Central Nervous System (CNS). However, its effects against Alzheimer's Disease (AD) still lack substantial evidence and in-depth exploration. The present study aimed to investigate the impacts of HPC on AD-related memory decline and amyloid-β (Aβ) pathology in AβPP/PS1 transgenic mice. Methods: Seven-week-old AβPP/PS1 transgenic mice were randomized into HPC and non-HPC groups. The HPC groups were treated with early and repetitive HPC for four weeks, while the non-HPC group was raised under normoxia condition. All the animals were then raised until the age of 28 weeks when Morris water maze tests were conducted to examine the animals’ spatial memory. Indicators for Aβ pathology (soluble Aβ levels and numbers of Aβ plaques) and the expression of relevant proteins were measured to explore potential mechanisms. Results: The results showed that HPC ameliorated memory decline and Aβ pathology in AβPP/PS1 mice. The protein levels of Amyloid-β Precursor Protein (AβPP) and β-site APP Cleaving Enzyme 1 (BACE1) were reduced while that of Hypoxic inducible factor 1α (HIF-1α) was elevated in HPC groups. Conclusion: HPC might be a promising strategy for AD intervention. Its potential protection might be realized via downregulating the expressions of AβPP and BACE1 and hence inhibiting Aβ pathology. Notably, HIF-1α might play a key role in mediating subsequent neuroadaptive changes following HPC.

Objectives: The study aimed to evaluate and quantify the temporal link between cognitive and functional decline, and assess the impact of the apolipoprotein E4 (APOE-e4) genotype on Alzheimer’s disease (AD) progression. Methods: A nonlinear mixed-effects Emax model was developed using longitudinal data from 659 patients with dementia due to AD sourced from the Alzheimer's disease neuroimaging initiative (ADNI) database. A cognitive decline model was first built using a cognitive subscale of the AD assessment scale (delayed word recall) as the endpoint, followed by a functional decline model, using the functional assessment questionnaire (FAQ) as the endpoint. Individual and population cognitive decline from the first model drove a functional decline in the second model. The impact of the APOE-e4 genotype status on the dynamics of AD progression was evaluated using the model. Results: Mixed-effects Emax models adequately quantified population average and individual disease trajectories. The model captured a higher initial cognitive impairment and final functional impairment in APOE-e4 carriers than non-carriers. The age at cognitive decline and diagnosis of dementia due to AD was significantly lower in APOE-e4 carriers than that of non-carriers. The average [standard deviation] time shift between cognitive and functional decline, i.e. the time span between half of the maximum cognitive decline and half of the maximum functional decline, was estimated as 1.5 [1.6] years. Conclusion: The present analysis quantifies the temporal link between a cognitive and functional decline in AD progression at the population and individual level, and provides information about the potential benefits of pre-clinical AD treatments on both cognition and function.

Background: Current conventional cognitive assessments are limited in their efficiency and sensitivity, often relying on a single score such as the total correct items. Typically, multiple features of response go uncaptured. Objectives: We aim to explore a new set of automatically derived features from the Digit Span (DS) task that address some of the drawbacks in the conventional scoring and are also useful for distinguishing subjects with Mild Cognitive Impairment (MCI) from those with intact cognition. Methods: Audio-recordings of the DS tests administered to 85 subjects (22 MCI and 63 healthy controls, mean age 90.2 years) were transcribed using an Automatic Speech Recognition (ASR) system. Next, five correctness measures were generated from Levenshtein distance analysis of responses: number correct, incorrect, deleted, inserted, and substituted words compared to the test item. These per-item features were aggregated across all test items for both Forward Digit Span (FDS) and Backward Digit Span (BDS) tasks using summary statistical functions, constructing a global feature vector representing the detailed assessment of each subject’s response. A support vector machine classifier distinguished MCI from cognitively intact participants. Results: Conventional DS scores did not differentiate MCI participants from controls. The automated multi-feature DS-derived metric achieved 73% on AUC-ROC of the SVM classifier, independent of additional clinical features (77% when combined with demographic features of subjects); well above chance, 50%. Conclusion: Our analysis verifies the effectiveness of introduced measures, solely derived from the DS task, in the context of differentiating subjects with MCI from those with intact cognition.

Background: Research indicates that polygenic indices of risk of Alzheimer’s disease are linked to clinical profiles. Objective: Given the “genetic centrality” of the APOE gene, we tested whether this held true for both APOE-ε4 carriers and non-carriers. Methods: A polygenic hazard score (PHS) was extracted from 784 non-demented participants recruited in the Alzheimer’s Disease Neuroimaging Initiative and stratified by APOE ε4 status. Datasets were split into sub-cohorts defined by clinical (unimpaired/MCI) and amyloid status (Aβ+/Aβ-). Linear models were devised in each sub-cohort and for each APOE-ε4 status to test the association between PHS and memory, executive functioning and grey-matter volumetric maps. Results: PHS predicted memory and executive functioning in ε4ε3 MCI patients, memory in ε3ε3 MCI patients, and memory in ε4ε3 Aβ+ participants. PHS also predicted volume in sensorimotor regions in ε3ε3 Aβ+ participants. Conclusion: The link between polygenic hazard and neurocognitive variables varies depending on APOE-ε4 allele status. This suggests that clinical phenotypes might be influenced by complex genetic interactions.

Background: The deterioration of cognitive and motor functions and activities of daily living is common in Alzheimer's dementia. Objectives: The purpose of this study was to investigate the correlation and the strength of the relationship between cognitive function and motor function and activities of daily living after a diagnosis of Alzheimer's disease dementia. Methods: Sixty-three patients with mild to moderate Alzheimer's disease dementia in a community setting of South Korea were examined for cognitive and motor functions, and functional levels. The test or measures used for cognitive function were the Mini-Mental State Examination (MMSE), Global Deterioration Scale (GDS), and Clinical Dementia Rating (CDR). The 10-meter walking test (10MWT), Berg Balance Scale (BBS), and Timed Up and Go Test (TUG) were used to examine motor function, while the Modified Barthel Index (MBI) and Katz Index (KI) were used to examining activities of daily living. Results: The MMSE had a positive correlation with that from the BBS (r=.338, p<.05), MBI (r=.363, p<.05), and KI (r=.276, p<.05). The GDS was negatively correlated with BBS (r=.319, p<.05). Multivariate regression analysis showed that MMSE was a major explanatory variable for BBS (R2 =.115, β=.338, p<.05) MBI (R2 =.131, β=.363, p<.05), and KI (R2 =.076, β=.276, p<.05). Conclusion: The results of the present study show that cognitive function by MMSE is correlated with balance by BBS and activities of daily living by MBI and KI, and MMSE, which are tests or measures for cognitive function, can be explanatory variable to explain variations in the BBS, MBI, and KI in the persons with mild to moderate Alzheimer’s dementia. It may mean that a decrease in cognitive function was found to affect motor function and activities of daily living. Based on this study, appropriate intervention approaches including physical exercise, should be considered for caring for persons with mild to moderate Alzheimer’s dementia in a community setting.