STUDYING THE ROLE OF ApoE IN ALZHEIMER'S DISEASE PATHOGENESIS USING A SYSTEMS BIOLOGY MODEL

Alzheimer's disease (AD) is the most common form of dementia. Even with its well-known symptoms of memory loss and well-characterized pathology of beta amyloid (Aβ) plaques and neurofibrillary tangles, the disease pathogenesis and initiating factors are still not well understood. To tackle this problem, a systems biology model has been developed and used to study the varying effects of variations in the ApoE allele present, as well as the effects of short term and periodic inflammation at low to moderate levels. Simulations showed a late onset peak of Aβ in the ApoE4 case that lead to localized neuron loss which could be ameliorated in part by application of short-term pro-inflammatory mediators. The model that has been developed herein represents one of the first attempts to model AD from a systems approach to study physiologically relevant parameters that may prove useful to physicians in the future.

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Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer’s Disease

Current Protein and Peptide Science ◽

10.2174/1389203721666200921152246 ◽

2020 ◽

Vol 21 (12) ◽

pp. 1164-1173

Author(s):

Siju Ellickal Narayanan ◽

Nikhila Sekhar ◽

Rajalakshmi Ganesan Rajamma ◽

Akash Marathakam ◽

Abdullah Al Mamun ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Early Onset ◽

Late Onset ◽

Precursor Protein ◽

Brain Disorder ◽

Amyloid Aβ ◽

T Tau

: Alzheimer’s disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

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Integrated Systems Approach Reveals Sphingolipid Metabolism Pathway Dysregulation in Association with Late-Onset Alzheimer’s Disease

Biology ◽

10.3390/biology7010016 ◽

2018 ◽

Vol 7 (1) ◽

pp. 16 ◽

Cited By ~ 1

Author(s):

◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Systems Approach ◽

Late Onset ◽

Integrated Systems ◽

Sphingolipid Metabolism ◽

Metabolism Pathway ◽

Pathway Dysregulation

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Diﬃculties in diagnosing atypical variants of Alzheimer’s disease

Russian neurological Journal ◽

10.30629/2658-7947-2021-26-5-16-23 ◽

2021 ◽

Vol 26 (5) ◽

pp. 16-23

Author(s):

A. A. Tappakhov ◽

T. Ya. Nikolaeva ◽

T. E. Popova ◽

N. A. Shnayder

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Picture ◽

Short Term Memory ◽

Late Onset ◽

Early Stage ◽

Primary Progressive Aphasia ◽

Cortical Atrophy ◽

Posterior Cortical Atrophy ◽

Short Term

Alzheimer’s disease (AD) is the most common cause of dementia in the population. Late onset AD has a classic clinical picture with short-term memory deficit, apraxia and agnosia. Patients with early-onset AD may have an atypical clinical picture which complicates diagnosis. Atypical AD variants include the logopenic variant of primary progressive aphasia, posterior cortical atrophy, behavioral, biparietal, and cortico-basal variants. These variants have pathomorphological signs similar to classical AD, but at an early stage they are characterized by focal atrophy which explains their clinical polymorphism. This article provides a review of the current literature on atypical types of AD and presents a clinical case of a 62-year-old patient in whom the disease debuted with prosopagnosia due to focal atrophy of the temporo-occipital regions of the non-dominant hemisphere.

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Autophagy and mitophagy biomarkers are reduced in sera of patients with Alzheimer’s disease and mild cognitive impairment

Scientific Reports ◽

10.1038/s41598-019-56614-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 11

Author(s):

Massimiliano Castellazzi ◽

Simone Patergnani ◽

Mariapina Donadio ◽

Carlotta Giorgi ◽

Massimo Bonora ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Late Onset ◽

Memory Loss ◽

Serum Levels ◽

Enzyme Linked Immunosorbent Assay ◽

Serum Samples ◽

Cellular Processes

AbstractDementia is a neurocognitive disorder characterized by a progressive memory loss and impairment in cognitive and functional abilities. Autophagy and mitophagy are two important cellular processes by which the damaged intracellular components are degraded by lysosomes. To investigate the contribution of autophagy and mitophagy in degenerative diseases, we investigated the serum levels of specific autophagic markers (ATG5 protein) and mitophagic markers (Parkin protein) in a population of older patients by enzyme-linked immunosorbent assay. Two hundred elderly (≥65 years) outpatients were included in the study: 40 (20 F and 20 M) with mild-moderate late onset Alzheimer’s disease (AD); 40 (20 F and 20 M) affected by vascular dementia (VAD); 40 with mild cognitive impairment (MCI); 40 (20 F and 20 M) with “mixed” dementia (MD); 40 subjects without signs of cognitive impairment were included as sex-matched controls. Our data indicated that, in serum samples, ATG5 and Parkin were both elevated in controls, and that VAD compared with AD, MCI and MD (all p < 0.01). Patients affected by AD, MD, and MCI showed significantly reduced circulating levels of both ATG5 and Parkin compared to healthy controls and VAD individuals, reflecting a significant down-regulation of autophagy and mitophagy pathways in these groups of patients. The measurement of serum levels of ATG5 and Parkin may represent an easily accessible diagnostic tool for the early monitoring of patients with cognitive decline.

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Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.abb9036 ◽

2020 ◽

Vol 6 (33) ◽

pp. eabb9036

Author(s):

Bradlee L. Heckmann ◽

Brett J. W. Teubner ◽

Emilio Boada-Romero ◽

Bart Tummers ◽

Clifford Guy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Disease ◽

Memory Impairment ◽

Memory Loss ◽

Tau Hyperphosphorylation ◽

Primary Microglia ◽

Amyloid Aβ ◽

Β Amyloid ◽

Old Mice

Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer’s disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease.

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A comparison of β-amyloid (Aβ) deposition in the medial temporal lobe in late-onset sporadic Alzheimer's disease, and Down's syndrome

Amyloid ◽

10.3109/13506129509031895 ◽

1995 ◽

Vol 2 (2) ◽

pp. 107-113 ◽

Cited By ~ 3

Author(s):

Richard A. Armstrong

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Late Onset ◽

Down's Syndrome ◽

Down’S Syndrome ◽

Sporadic Alzheimer’S Disease ◽

Amyloid Aβ ◽

Β Amyloid

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Patients with Alzheimer's disease have increased cellular amyloid uptake

10.1101/2022.01.12.22269196 ◽

2022 ◽

Author(s):

Dmitry V Zaretsky ◽

Maria V Zaretskaia ◽

Yaroslav I Molkov

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Late Onset ◽

Strong Negative Correlation ◽

Cognitively Normal ◽

Intracellular Degradation ◽

Estimated Parameters ◽

Amyloid Aβ ◽

Using Data

Amyloid plaques are the main signature of Alzheimer's disease (AD). Beta-amyloid (Aβ) concentration in cerebrospinal fluid (CSF-Aβ) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-Aβ levels compared to cognitively normal people even after accounting for this correlation. The goal of this study was to infer variations of parameters in Aβ metabolism of AD patients that underlie this difference using data from the Alzheimer's Disease Neuroimaging Initiative cohort. We found that AD patients had dramatically increased rates of cellular amyloid uptake compared to individuals with normal cognition (NC). A group with late-onset mild cognitive impairment (LMCI) also exhibited stronger amyloid uptake, however this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group. Aβ cytotoxicity depends on both the amount of peptide internalized by cells and its intracellular degradation into toxic products. Based on our results, we speculate that AD and LMCI are associated with increased cellular amyloid uptake which leads to faster disease progression, whereas the early-onset MCI may be mediated by the increased production of toxic amyloid metabolites.

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P2-105: A NOVEL SYSTEMS BIOLOGY APPROACH TO EVALUATE MOUSE MODELS OF LATE ONSET ALZHEIMER'S DISEASE: NCOUNTER MOUSE AD PANEL

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.2512 ◽

2019 ◽

Vol 15 ◽

pp. P612-P613

Author(s):

Christoph Preuss ◽

Ravi S. Pandey ◽

Alexander Fine ◽

Asli Uyar ◽

Benjamin A. Logsdon ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Systems Biology ◽

Mouse Models ◽

Late Onset

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Epigenetic Factors in Late-Onset Alzheimer’s Disease: MTHFR and CTH Gene Polymorphisms, Metabolic Transsulfuration and Methylation Pathways, and B Vitamins

International Journal of Molecular Sciences ◽

10.3390/ijms20020319 ◽

2019 ◽

Vol 20 (2) ◽

pp. 319 ◽

Cited By ~ 15

Author(s):

Gustavo Román ◽

Oscar Mancera-Páez ◽

Camilo Bernal

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Methylenetetrahydrofolate Reductase ◽

Late Onset ◽

Memory Loss ◽

B Vitamins ◽

Common Mutation ◽

Epigenetic Factors ◽

Vitamin B9 ◽

Transsulfuration Pathway

DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer’s disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-l-methionine (SAM), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase (CTH) gene affects the enzyme that converts cystathionine to cysteine in the transsulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia—a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins. We emphasize the importance of supplementing vitamin B12 (methylcobalamin), vitamin B9 (folic acid), vitamin B6 (pyridoxine), and SAM to patients in early stages of LOAD.

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