Common Form Of Alzheimer's Disease Research Articles

Chronic Administration of Scopolamine Increased GSK3βP9, Beta Secretase, Amyloid Beta, and Oxidative Stress in the Hippocampus of Wistar Rats.

The increase of amyloid beta (Aβ) release and hyperphosphorylation of Tau protein represents the main events related to Alzheimer's disease (AD). Furthermore, the sporadic type represents the most common form of AD. Therefore, the establishment of a non-transgenic animal model that resembles the characteristics of the disease is of particular importance. Scopolamine has been linked to increases in both Aβ production and oxidative stress in rat and mice brains. Thus, the purpose of the present work was to identify changes in biomarkers that are related to AD after chronic administration of scopolamine (2mg/kg i.p., during 6 and 12weeks) to male Wistar rats. The results showed increased Aβ deposition at rat hippocampus which could be due to an increase of β-site amyloid-β-protein precursor cleaving enzyme 1 (BACE1) expression and activity. These findings could be related to the increase of glycogen synthase kinase 3 phosphorylated (GSK3βP9) expression. Finally, the establishment of a state of oxidative stress in groups treated with scopolamine was demonstrated by an increase in free radical content and MDA levels. The present study facilitates our understanding of the changes that occur in biomolecules related to AD in Wistar rats after the chronic administration of scopolamine.

EVALUATING THE ASSOCIATION BETWEEN MITOCHONDRIAL DYSFUNCTION AND COGNITIVE DECLINE IN ALZHEIMER'S DISEASE

Introduction Alzheimer's Disease (AD) is the 6th leading cause of death in the United States, with the current number of 5.8?million affected individuals anticipated to increase to 13.8?million by 2050 (Alzheimer's Association, 2019). As the number of older adults living with Alzheimer's rapidly increases, research continues to probe the complexities of the disease's progression. AD was originally identified by the presence of amyloid plaques and neurofibrillary tangles in brain, and most research has focused on these elements. However, targeting amyloid cascade and tau phosphorylation has not resulted in the development of drugs that have halted or reversed the cognitive decline associated with AD (Du, Wang, & Geng, 2018). AD has multiple determinants, and, in most cases, plaques and tangles may not be secondary to other underlying processes. The focus of our research is investigating the role of cellular energy dysfunction in the etiology and progression of AD. Preliminary findings from our group, Sonntag and colleagues (2017), revealed changes in energy metabolism (or bioenergetics) in the fibroblasts of 10 patients with late-onset Alzheimer's Disease, the most common form of AD, compared to 20 age-matched controls, with implications of impaired mitochondrial metabolic potential as a possible contributor to the pathophysiology of AD. The present study builds on the prior work of Sonntag et al, aiming to confirm previous findings with additional samples of fibroblasts and lymphocytes from older adults with mild to moderate Alzheimer's Disease. The cells gathered are being converted to brain cells, neurons and glia, to determine whether the abnormalities seen in peripheral lines are also seen in the brain. In collaboration with the Geriatric Psychiatry Research Program at McLean, data obtained from the collected samples will be analyzed alongside the results from brain imaging data (specifically, MRI and amyloid PET scan) and clinical measures of the participants as supporting evidence in the link between mitochondrial dysfunction and cognitive decline in AD. Methods This study aims to enroll a total of 40 subjects (ages 65 to 89): 20 control subjects and 20 subjects diagnosed with mild to moderate Alzheimer's Disease. Enrolled subjects will undergo the following scales to assess for comorbid psychiatric disorders and their severity: Montgomery-Asberg Depression Rating Scale (MADRS),Young Mania Rating Scale (YMRS), Geriatric Depression Scale (GDS) and the Mini-International Neuropsychiatric Interview (MINI). The Montreal Cognitive Assessment (MOCA) is also performed to determine study suitability. Once inclusion criteria are met for both populations, samples of skin and blood will be collected and subsequently processed to grow cell lines of fibroblasts and lymphocytes. These cells are reprogrammed to induced pluripotent stem cell lines (iPSC) and then to neuronal and glial lines. Results Though ongoing, we anticipate similar results to Sonntag et al. (2017), as genetic determinants are shared among peripheral and CNS cells. In culture, both genetic and exogenous risk factors can be studied. As a secondary result, a correlation is anticipated between the bioenergetic abnormalities observed in the cells and in the brain imaging data and clinical measures of the participants. These findings may support the association between mitochondrial dysfunction and the cognitive decline in Alzheimer's Disease among a larger sample size. Conclusions Identifying the mitochondrial dysfunction in Alzheimer's Disease not only contributes a new explanation for its complex pathophysiology, complementary to other hypotheses, but provides a new direction for the development of novel treatments to effectively target the devastating effects of cognitive decline in AD. This research was funded by: This study is funded by the Program for Neuropsychiatric Research at McLean Hospital

DYSREGULATION OF THE Aβ DEGRADING ENZYME NEPRILYSIN (MME) COULD CONTRIBUTE TO ALZHEIMER’S DISEASE

Alzheimer's disease (AD) is the foremost world-wide cause of age-related dementia. Its global prevalence constantly on the increase due to an aging population. Among the dementias, AD is characterized by accumulation of amyloid β (Aβ) plaques and aggregates of hyper-phosphorylated microtubule-associated protein tau (p-τ) in brains. Nevertheless, the underlying pathogenesis of AD is presently unknown, particularly the most common form of AD, late-onset. Even though genetic, epigenetic, and environmental factors play critical roles in AD etiology (Maloney and Lahiri, Lancet Neurol-2016), specific triggers are still unknown. We hypothesize that AD results from dysregulation of key biochemical pathways, particularly through regulatory molecules, such as non-coding RNAs, including microRNA (Long, Maloney, Rogers and Lahiri, Mol. Psychiatry-2018). We further posit that disruption of miRNA regulation of membrane metallo-endopeptidase (MME), or neprilysin could contribute to Aβ accumulation and hence AD pathogenesis, since MME is an important Aβ-clearing enzyme. Using the bioinformatics tools we predicted miRNA binding sites on the MME mRNA 3’-untranslated region (3’-UTR). We made neuronally-differentiated human neuroblastoma (SK-N-SH) cells with all-trans retinoic acid (ATRA). We transfected the differentiated cells with either siRNA against MME or candidate miRNAs. We assayed levels of MME mRNA and its protein by qRT-PCR and Western blotting, respectively. Upon identifying miR-181d as a functional candidate, we tested sequence specificity and miR-181d activity with reporter gene- MME 3’-UTR constructs. We also measured MME protein levels in several human fetal tissues. While several miRNAs were predicted to target the MME 3’-UTR, including miR-9, miR-181d, miR-128 and miR-216, only miR-181d treatment produced significant reduction of MME mRNA and protein levels in neuronal cultures. The functional assays further elucidated miR181d activity. MME is expressed in a variety of human organs, with the highest expression in kidney. Notably, miR-181d can down-regulate MME mRNA and protein through the specific target site within MME 3’-UTR. MME is a key Aβ-degrading enzyme involved in AD. Dysregulation by (presumably excess) miR-181d could contribute to AD pathogenesis. Supported by the NIA/NIH grant to DKL.

CareD: Non-Pharmacological Assistance for Dementia Patients

BACKGROUND: Dementia is a common form of Alzheimer disease which is affecting the quality of older adults’ life. Non-drug treatment such as cognitive therapies are more beneficial for such patients. These days, mobile applications are providing tremendous opportunities for aiding the medicinal treat

Effect of Alzheimer Familial Chromosomal Mutations on the Amyloid Fibril Interaction with Different PET Tracers: Insight from Molecular Modeling Studies.

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Along with an increasing number of elderly worldwide, it poses a great challenge for the society and health care. Although sporadic AD is the common form of AD, 2-3% of the AD cases are expected to be due to mutations in the β region of the amyloid precursor protein, which is referred to as autosomal dominant AD (ADAD). These mutations may cause changes in the secondary structure of the amyloid β fibrils and may alter the fibrillization rate leading to changes in the disease development and could also affect the binding to tracers used in diagnosis. In particular, from some recent clinical studies using PET tracers for detection of fibrillar amyloids, it is evident that in ADAD patients with Arctic mutation no amyloid plaque binding can be detected with the 11C-Pittsburgh Compound B (11C-PIB). However, for in vitro conditions, significant binding of 3H-PIB has been reported for the amyloid fibrils carrying the Arctic mutation. The aim of the present study is to investigate if there is any mutation specific binding of commonly used amyloid tracers, namely, florbetaben, florbetapir, FPIB, AZD4694, and AZD2184, by means of molecular modeling techniques. Other than Arctic, ADAD mutations, such as the Dutch, Italian, Iowa, and Flemish mutations, are considered in this study. We report that all tracers except florbetapir show reduced binding affinity toward amyloid β fibrils with the Arctic mutation when compared to the native type. Moreover, florbetapir is the only tracer that binds to all mutants with increased affinity when compared to the native fibril. The results obtained from these studies could increase the understanding of the structural changes caused by mutation and concomitant changes in the interaction pattern of the PET tracers with the mutated variants, which in turn can be useful in selecting the appropriate tracers for the purpose of diagnosis as well as for designing new tracers with desirable properties.

POTENTIAL NON-CLASSICAL BIOMARKERS IN THE CEREBROSPINAL FLUID OF SPORADIC ALZHEIMER’S DISEASE

Sporadic Alzheimer disease (AD) is the most common form of AD, yet its causes are currently unknown. Several studies have indicated that abnormal levels of electrolytes and transition metals may play a role in the pathogenesis of AD. It has been shown that altered homeostasis of brain copper, zinc, and particularly, iron, can generate oxidative stress, a process that has been linked to the pathogenesis of sporadic AD. We have obtained samples of cerebrospinal fluids (CSF) from well-defined AD patients (n=8) and control patients (n=7). Atomic elements (Na, K, Ca, Mg, Cu, Fe, Mn, Zn and Al) were measured by flame or graphite furnace atomic absorption spectrometry. SOD activity was measured spectrophotometrically. We have observed that, compared to controls, K and Fe levels were significantly increased in the CSF of AD individuals, while the concentration of Zn and Al were decreased. Further, we observed that total SOD activity was elevated CSF from AD individuals. We have demonstrated the existence of disturbances in the concentrations of K, Fe and Zn, total protein and SOD activity in AD subjects, compared to controls. Therefore ionic markers and their relationship with classical and oxidative stress biomarkers could provide new diagnostic tools for AD.

Autosomal Dominant Alzheimer Disease: A Unique Resource to Study CSF Biomarker Changes in Preclinical AD.

Our understanding of the pathogenesis of Alzheimer disease (AD) has been greatly influenced by investigation of rare families with autosomal dominant mutations that cause early onset AD. Mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) cause over-production of the amyloid-β peptide (Aβ) leading to early deposition of Aβ in the brain, which in turn is hypothesized to initiate a cascade of processes, resulting in neuronal death, cognitive decline, and eventual dementia. Studies of cerebrospinal fluid (CSF) from individuals with the common form of AD, late-onset AD (LOAD), have revealed that low CSF Aβ42 and high CSF tau are associated with AD brain pathology. Herein, we review the literature on CSF biomarkers in autosomal dominant AD (ADAD), which has contributed to a detailed road map of AD pathogenesis, especially during the preclinical period, prior to the appearance of any cognitive symptoms. Current drug trials are also taking advantage of the unique characteristics of ADAD and utilizing CSF biomarkers to accelerate development of effective therapies for AD.

Could Clinical Profile Influence CSF Biomarkers in Early-onset Alzheimer Disease?

In common forms of Alzheimer disease (AD), anterograde memory impairment is the first deficit to occur. However, the disease, especially in its presenile forms, may also manifest itself through initial deficits that are predominantly of a nonmemory type. These distinct clinical profiles, which reflect the distinct topography of the underlying pathologic processes, may also differ in terms of their cerebrospinal fluid (CSF) markers. The aim of this study was to assess the levels of total tau, phosphorylated tau, and amyloid-beta 42 peptide in the CSF of "atypical" (nonmemory) early-onset AD patients. CSF biomarkers were evaluated in 22 atypical patients, and compared with those from a group of 13 "typical" patients, with a memory onset form of the disease. Our results show that independently of age, disease duration, education level, and clinical severity indices, patients with an atypical onset have significantly higher levels of total tau in the CSF (P=0.023). These findings indicate that an assessment of CSF biomarkers may be of particular use in the clinical diagnosis of "atypical-onset" forms of early-onset AD in which the initial symptoms involve language and visuospatial abilities rather than memory. In addition, they highlight the heterogeneity of pathologic processes in AD, suggesting more intense degeneration in the forms of the disease that primarily involve neocortical structures.

Early Amyloid Accumulation in the Hippocampus of SAMP8 Mice

Late-onset Alzheimer's disease (AD) is the most common form of AD appearing after 65 years of age. To date, however, there are no non-genetically manipulated rodent models that develop a similar sporadic onset of AD with age-related amyloid-beta (Abeta) deposition. Although the senescence accelerated mouse prone 8 (SAMP8) mice have been proposed as a model of AD, the presence of Abeta deposits remains controversial. In this study, we describe the time course of Abeta deposition in SAMP8 mice as well as in control SAMR1 and ICR-CD1 strains of mice. From as early as 6 months onward, SAMP8 mice show Abeta deposition in the hippocampus that increase in number and extent with age. These deposits are comprised of by clustered granules that contain Abeta{42}, Abeta{40}, and other Abeta protein precursor fragments. By marked contrast, control mice show only low numbers of Abeta clusters that do not develop until 15 months of age. The demonstration that SAMP8 mice present with amyloid deposits in their hippocampus makes this animal model a useful tool to understand the mechanisms involved in Abeta deposition in AD.

Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo

Certain disease states are characterized by disturbances in production, accumulation or clearance of protein. In Alzheimer disease, accumulation of amyloid-beta (Abeta) in the brain and disease-causing mutations in amyloid precursor protein or in enzymes that produce Abeta indicate dysregulation of production or clearance of Abeta. Whether dysregulation of Abeta synthesis or clearance causes the most common form of Alzheimer disease (sporadic, >99% of cases), however, is not known. Here, we describe a method to determine the production and clearance rates of proteins within the human central nervous system (CNS). We report the first measurements of the fractional production and clearance rates of Abeta in vivo in the human CNS to be 7.6% per hour and 8.3% per hour, respectively. This method may be used to search for novel biomarkers of disease, to assess underlying differences in protein metabolism that contribute to disease and to evaluate treatments in terms of their pharmacodynamic effects on proposed disease-causing pathways.

Solvent-Free Mass Spectrometry for Hydrophobic Peptide Sequence Analysis and Protein Conformation Studies

Solvent-Free Mass Spectrometry for Hydrophobic Peptide Sequence Analysis and Protein Conformation Studies

The Low Density Lipoprotein Receptor Regulates the Level of CentralNervous System Human and Murine Apolipoprotein E but Does Not Modify AmyloidPlaque Pathology in PDAPPMice

Apolipoprotein E (apoE), a chaperone for the amyloid beta (Abeta) peptide, regulates the deposition and structure of Abeta that deposits in the brain in Alzheimer disease (AD). The primary apoE receptor that regulates levels of apoE in the brain is unknown. We report that the low density lipoprotein receptor (LDLR) regulates the cellular uptake and central nervous system levels of astrocyte-derived apoE. Cells lacking LDLR were unable to appreciably endocytose astrocyte-secreted apoE-containing lipoprotein particles. Moreover, cells overexpressing LDLR showed a dramatic increase in apoE endocytosis and degradation. We also found that LDLR knock-out (Ldlr-/-) mice had a significant, approximately 50% increase in the level of apoE in the cerebrospinal fluid and extracellular pools of the brain. However, when the PDAPP mouse model of AD was bred onto an Ldlr-/- background, we did not observe a significant change in brain Abeta levels either before or after the onset of Abeta deposition. Interestingly, human APOE3 or APOE4 (but not APOE2) knock-in mice bred on an Ldlr-/- background had a 210% and 380% increase, respectively, in the level of apoE in cerebrospinal fluid. These results demonstrate that central nervous system levels of both human and murine apoE are directly regulated by LDLR. Although the increase in murine apoE caused by LDLR deficiency was not sufficient to affect Abeta levels or deposition by 10 months of age in PDAPP mice, it remains a possibility that the increase in human apoE3 and apoE4 levels caused by LDLR deficiency will affect this process and could hold promise for therapeutic targets in AD.

The role of cerebral amyloid β accumulation in common forms of Alzheimer disease

For approximately 80 years following Alzheimer's description of the disease that bears his name, a gulf divided researchers who believed that extracellular deposits of the amyloid beta (Abeta) peptide were pathogenic from those who believed that the deposits were secondary detritus. Since 1990, the discoveries of missense mutations in the Abeta peptide precursor (APP) and the APP-cleaving enzyme presenilin 1 (PS1) have enabled much progress in understanding the molecular, cellular, and tissue pathology of the aggregates that accumulate in the interstices of the brains of patients with autosomal dominant familial Alzheimer disease (AD). Clarification of the molecular basis of common forms of AD has been more elusive. The central questions in common AD focus on whether cerebral and cerebrovascular Abeta accumulation is (a) a final neurotoxic pathway, common to all forms of AD; (b) a toxic by-product of an independent primary metabolic lesion that, by itself, is also neurotoxic; or (c) an inert by-product of an independent primary neurotoxic reaction. Antiamyloid medications are entering clinical trials so that researchers can evaluate whether abolition of cerebral amyloidosis can mitigate, treat, or prevent the dementia associated with common forms of AD. Successful development of antiamyloid medications is critical for elucidating the role of Abeta in common AD.

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

For approximately 80 years following Alzheimer’s description of the disease that bears his name, a gulf divided researchers who believed that extracellular deposits of the amyloid β (Aβ) peptide were pathogenic from those who believed that the deposits were secondary detritus. Since 1990, the discoveries of missense mutations in the Aβ peptide precursor (APP) and the APP-cleaving enzyme presenilin 1 (PS1) have enabled much progress in understanding the molecular, cellular, and tissue pathology of the aggregates that accumulate in the interstices of the brains of patients with autosomal dominant familial Alzheimer disease (AD). Clarification of the molecular basis of common forms of AD has been more elusive. The central questions in common AD focus on whether cerebral and cerebrovascular Aβ accumulation is (a) a final neurotoxic pathway, common to all forms of AD; (b) a toxic by-product of an independent primary metabolic lesion that, by itself, is also neurotoxic; or (c) an inert by-product of an independent primary neurotoxic reaction. Antiamyloid medications are entering clinical trials so that researchers can evaluate whether abolition of cerebral amyloidosis can mitigate, treat, or prevent the dementia associated with common forms of AD. Successful development of antiamyloid medications is critical for elucidating the role of Aβ in common AD.

Endocytic Pathway Abnormalities Precede Amyloid β Deposition in Sporadic Alzheimer’s Disease and Down Syndrome: Differential Effects of APOE Genotype and Presenilin Mutations

Endocytosis is critical to the function and fate of molecules important to Alzheimer's disease (AD) etiology, including the beta protein precursor (betaPP), amyloid beta (Abeta) peptide, and apolipoprotein E (ApoE). Early endosomes, a major site of Abeta peptide generation, are markedly enlarged within neurons in the Alzheimer brain, suggesting altered endocytic pathway (EP) activity. Here, we show that neuronal EP activation is a specific and very early response in AD. To evaluate endocytic activation, we used markers of internalization (rab5, rabaptin 5) and recycling (rab4), and found that enlargement of rab5-positive early endosomes in the AD brain was associated with elevated levels of rab4 immunoreactive protein and translocation of rabaptin 5 to endosomes, implying that both endocytic uptake and recycling are activated. These abnormalities were evident in pyramidal neurons of the neocortex at preclinical stages of disease when Alzheimer-like neuropathology, such as Abeta deposition, was restricted to the entorhinal region. In Down syndrome, early endosomes were significantly enlarged in some pyramidal neurons as early as 28 weeks of gestation, decades before classical AD neuropathology develops. Markers of EP activity were only minimally influenced by normal aging and other neurodegenerative diseases studied. Inheritance of the epsilon4 allele of APOE, however, accentuated early endosome enlargement at preclinical stages of AD. By contrast, endosomes were normal in size at advanced stages of familial AD caused by mutations of presenilin 1 or 2, indicating that altered endocytosis is not a consequence of Abeta deposition. These results identify EP activation as the earliest known intraneuronal change to occur in sporadic AD, the most common form of AD. Given the important role of the EP in Abeta peptide generation and ApoE function, early endosomal abnormalities provide a mechanistic link between EP alterations, genetic susceptibility factors, and Abeta generation and suggest differences that may be involved in Abeta generation and beta amyloidogenesis in subtypes of AD.

Alzheimer's disease as a polygenic disease

Recent advances in molecular genetics have enabled the identification of the causative genes for early‐onset familial Alzheimer's disease (AD). However, sporadic and late‐onset familial AD, the most common forms of AD, are considered to be polygenic disorders. The presence of APOE4, one of the specific alleles of the apolipoprotein E gene, has been established as a major genetic risk factor for the development of AD. Additional risk factors are under active investigation. Such new approaches are expected to establish preventive measures or treatments for AD.

A model for susceptibility polymorphisms for complex diseases: apolipoprotein E and Alzheimer disease.

Apolipoprotein E (APOE) polymorphisms are associated with variable risk and age of onset distributions for the common form of Alzheimer disease. Clinical genetic applications of APOE genotyping differ from those of family-specific mutations because the APOE genotypes are universally distributed in all populations, with ethnic and racial variations in relative allele frequencies. The association of a common disease affecting millions of people with genetic risk factors provides a new paradigm for understanding disease pathogenesis and an opportunity to focus on relevant genetic mechanisms. Clinical applications of APOE genotype information are based on epidemiological principles, rather than family-specific genetic counselling. At the present time it is not possible to predict when or if any individual will develop AD. Likewise, no APOE genotype provides escape from risk. However, an impending ethical and social dilemma is on the near horizon. When additional susceptibility polymorphisms are found, for example within a recently reported linkage to a chromosome 12 region, disease prediction may be possible for millions of unaffected individuals at a time when preventive therapies are not yet available. This impending capability should be a wake-up call for anticipating social, ethical, and legal problems. It differs from the current model of family specific mutations because, rather than affecting a relatively small population at risk, millions of people will be capable of receiving favorable or unfavorable prognostic information. The association of common polymorphisms with complex diseases finds its first example in APOE and AD. Just as the linkage search for other susceptibility genes can be modelled after AD, the medical, ethical, social, and legal implications of this paradigm can serve as a template for other complex disease loci being actively sought by industry and in academic laboratories.

Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis

In 1911, Alois Alzheimer published a detailed report (Zbl. ges. Neurol. Psych. 4: 356-385) on a peculiar case of the disease that had been named after him by Emil Kraepelin in 1910. Alzheimer describes a 56-year-old male patient (Johann F.) who suffered from presenile dementia and who was hospitalized in Kraepelin's clinic for more than 3 years. Post-mortem examination of the patient's brain revealed numerous amyloid plaques but no neurofibrillary tangles in the cerebral cortex, corresponding to a less common form of Alzheimer disease which may be referred to as 'plaque only'. We have identified well-preserved histological sections of this case and performed mutational screening of exon 17 of the amyloid precursor protein gene and genotyping for apolipoprotein E alleles. The patient was shown to be homozygous for apolipoprotein allele epsilon3 and lacked APP mutations at codons 692, 693, 713 and 717. This case is of historical importance as it may have convinced Kraepelin to name the disease after his co-worker, Alois Alzheimer.

No association between alpha 1-antichymotrypsin and familial Alzheimer's disease.

Alzheimer's disease (AD) is the most common mid to late age-of-onset neurodegenerative disorder. AD has a strong and complex genetic etiology, and multiple genes, acting independently and/or interacting, likely affect the risk of developing AD. Several genes involved with AD already have been described, but only the APOE gene on chromosome 19q has been shown to affect the risk of the most common form of AD, occurring with onset over the age of 65. Because a substantial portion of late-onset AD is not explained by APOE, other genes affecting late-onset AD likely occur. These could act either independently or perhaps interact with APOE. alpha 1-Antichymotrypsin (ACT) is a major component of the amyloid plaques found in the brains of AD patients and may play a role in the pathophysiology of AD. It has been proposed that a specific polymorphism within the ACT gene interacts with APOE to increase the risk of developing AD. Our results do not confirm this finding.