Welcome to the AD/PD™ 2022 Interactive Program
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LOAD2: A NOVEL MOUSE MODEL FOR INVESTIGATING INTERACTIONS BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS FOR LATE-ONSET ALZHEIMER'S DISEASE
Abstract
Aims
MODEL-AD (Model Organism Development and Evaluation for Late-onset AD) is developing and characterizing novel mouse models that aim to better phenocopy human LOAD for preclinical testing.
Methods
APOE4 and Trem2*R47H were incorporated into C57BL/6J (B6) mice to produce LOAD1. A humanized amyloid-beta (Aβ) allele was added to LOAD1 mice to form the LOAD2 strain. Female and male LOAD1 and LOAD2 mice on control diet (CD) or high fat diet (HFD) are being assessed for behavior, cognition, in vivo imaging of brain perfusion and metabolism, fluid biomarkers, neuropathology, transcriptomics, metabolomics, proteomics, dendritic spine density and long-term potentiation (LTP) from 4-24 months of age (mos).
Results
Compared to other groups, at 12 mos, LOAD2 mice on HFD showed elevated levels of insoluble Aβ42. LOAD2 mice on HFD also showed reduced density of cortical neurons. These brain changes correlated with elevated levels of TNFa and IL10 in the plasma and neurofilament light chain in cerebral spinal fluid. At 24 mos, accumulation of human APP was observed in cortical neurons of LOAD2 mice on CD suggesting that Aβ processing and clearance may be perturbed. Both LTP and dendritic spine density were reduced from 4 mos in LOAD2 mice on CD similar to previous reports for APOE4 mice. However, these changes were not correlated with deficits in hippocampal spatial working memory.
Conclusions
The combination of aging, genetic risk (APOE4, Trem2*R47H, humanized Aβ) with HFD as an environmental risk induced age-dependent LOAD-relevant phenotypes making LOAD2 mice a useful tool for mechanistic studies and therapeutic testing.
REDUCED CSF AΒ42 AND AΒ42/AΒ40 RATIO DURING EARLY CEREBRAL AMYLOID DEPOSITION IN THE APP NL-F KNOCK-IN MOUSE MODEL OF ALZHEIMER’S DISEASE
Abstract
Aims
The concentration of Aβ42 in cerebrospinal fluid (CSF) is decreased at least a decade before cognitive symptoms caused by Alzheimer’s disease (AD) manifest. This drop in concentration has been suggested to occur before abnormal levels of fibrillar Aβ in the brain are reached, but the underlying cause is not well understood. The present study aims to explore the translational potential of a novel App knock-in mouse model for investigation of the early events in Aβ pathology that associates with reduced CSF Aβ42 in preclinical AD.
Methods
CSF and brain tissue was collected from 3-18 months old AppNL-F knock-in mice. CSF Aβ40 and Aβ42 concentrations were measured using Single Molecule Array (Simoa) technology. Immunohistochemistry and Thioflavin S staining was performed on brain sections for detection of Aβ42 and amyloid fibrils, respectively.
Results
CSF Aβ40 remained unchanged while CSF Aβ42 and Aβ42/Aβ40 ratio were reduced from 12 months of age after which a plateau was reached (Fig.1). The initial reduction coincided with early deposition of Aβ42 and fibrillar plaques in the brain that gradually increased with age (Fig.2).
Conclusions
CSF Aβ42 and Aβ42/Aβ40 ratio are reduced in AppNL-F knock-in mice and seems to reflect pathological processes that occur slightly before deposition of amyloid in the brain is widespread. This reduction quickly reaches a plateau, although accumulation of cerebral amyloid steadily continues to increase. These results are in good agreement with clinical findings, emphasizing the use of AppNL-F knock-in mice to further investigate the underlying cause of the change in these CSF biomarkers in preclinical AD.
SIRT6 ROLES IN PROTECTING THE BRAIN FROM NEURODEGENERATION
Abstract
Aims
Aging is the main risk factor for developing a neurodegenerative disease. We have shown that the brain-specific SIRT6-deficient (brSIRT6-KO) mice presenting memory impairments, increased DNA damage, cell death, Tau stabilization, and more resembling AD diseases. Importantly AD patients have significantly less SIRT6 in their brains. SIRT6 influences gene expression by its roles in chromatin remodeling and affects different targets directly through PTMs. Our aim is to understand the molecular changes occurring in aging brains that lead to neurodegeneration.
Methods
bioinformatics, molecular biology, behavior, biochemistry
Results
Our results define four gene expression categories that change with age in a pathological or non-pathological manner, some of which Calorie Restriction can reverse. Importantly, each gene expression category is associated with specific transcription factors, thus serving as potential candidates for their category. In addition, we discovered that SIRT6 could regulate Tau migration to the nucleus through its deacetylation activity in residue K174. We discover that Tau hyper-acetylation at residue 174, a modification increasing in AD patients and enhance its stability, increases Tau’s nuclear presence in a DNA damage-dependent manner. However, lack of SIRT6 or DNA damage results in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression, affecting protein translation, and energy production. This phenomenon was also observed in AD patients.
Conclusions
Overall, SIRT6 has various critical roles in protecting the brain from neurodegeneration. This model is important as a new tool to understand sporadic age-related AD cases, representing 95% of the total cases. It will be key to finding novel targets and treatments for neurodegeneration.
PM20D1-DERIVED TREATMENT DECREASES AMYLOID PATHOLOGY AND IMPROVES COGNITIVE PERFORMANCE IN C.ELEGANS AND MOUSE MODELS OF ALZHEIMER´S DISEASE
Abstract
Aims
Alzheimer’s disease (AD) is a complex disorder caused by a combination of genetic and non-genetic factors, which are investigated by genome- (GWAS) and epigenome- (EWAS) wide association studies, respectively. Combining the strengths of both type of studies, we have recently identified a new genetic-epigenetic interaction on Peptidase M20 Domain Containing 1 (PM20D1) associated with AD. We showed that PM20D1 expression depends on a haplotype-dependent chromatin loop between PM20D1 enhancer and promoter regions, that PM20D1 expression is increased by AD-like stressors, and that its overexpression improves cognitive performance and reduces AD pathologies. However, the precise mechanism by which PM20D1 exerts its protective role in AD remains largely unknown. PM20D1 facilitates the condensation of fatty acids and amino acids generating a series of compounds named N-acyl amino acids (NAAs). NAAs are present in all tissues, including brain, yet little is known about their function and regulation.
Methods
To investigate their role in AD, we NAA-treated AD primary cultures, worms and mouse models, and measured AD-related pathologies and cognitive performance. Furthermore, to unveil the underlying mechanisms, we applied snRNA-seq approaches and cell-type specific manipulations.
Results
Following this approach, we demonstrate that NAAs modify the cellular phase of AD and improves cell survival, amyloid burden and cognitive performance.
Conclusions
Our results therefore support the use of NAAs as a therapeutic approach for AD.
AΒETA OLIGOMER ELIMINATION IMPROVES COGNITION IN AGED BEAGLE DOGS - A MODEL OF SPORADIC ALZHEIMER’S DISEASE.
Abstract
Aims
Alzheimer´s Disease (AD) currently affects more than 24 million people worldwide, but to date, no curative or disease modifying treatment exists. During the last years, our group developed a drug candidate named RD2, which directly disassembles and destroys toxic Aβ oligomers, the Aβ species postulated to be responsible for the development and progression of AD. The aim of this study was to investigate the treatment efficacy of RD2 with regard to cognition and biomarkers in aged beagle dog - a model of sporadic AD -.
Methods
Aged beagle dogs were treated orally for three months with low or high doses of RD2 or placebo. Behavioral assessments were conducted longitudinally and CSF and plasma samples were collected at baseline and every month during the treatment period and during an additional two months after treatment discontinuation.
Results
Only RD2 treated dogs showed a significantly improved cognitive performance compared to baseline, even after the wash out period of two months.
Conclusions
We were able to show that RD2 significantly improves cognitive deficits in aged Beagle dogs. The maintenance of the cognitive improvement during the washout period even suggests a neuroprotective and truly disease-modifying effect of RD2.
A NOVEL MODEL OF CEREBRAL SMALL VESSEL DISEASE WITH WHITE MATTER HYPERINTENSITIES AND PERIPHERAL OXIDATIVE STRESS USING THE SABRA RATS
Abstract
Aims
Cerebral small vessel disease (CSVD) is the second most common cause of stroke and a major contributor to dementia. CSVD manifests in a variety of pathological mechanisms including cerebral microbleeds, intracerebral hemorrhages (ICH), lacunar infarcts, white matter hyperintensities (WMH) and enlarged perivascular spaces. Chronic hypertensive models were found to resemble most key features of the disease. Nevertheless, no animal models have been identified to reflect all different aspects of the human disease. We designed experiments for characterizing a novel model for CSVD, using salt-sensitive ‘Sabra’ hypertension-prone rats (SBH/y) which display chronic hypertension and enhanced peripheral oxidative stress.
Methods
SBH/y rats were either administered deoxycorticosteroid acetate (DOCA) (referred to as SBH/y-DOCA rats) or sham operated and provided with 1% NaCl in drinking water. Rats underwent neurological assessment and behavioral testing, followed by ex-vivo MRI, biochemical and histological analyses.
Results
SBH/y-DOCA rats show neurological decline and cognitive impairment, and present multiple cerebrovascular pathologies associated with CSVD such as ICH, lacunes, enlarged perivascular spaces, blood vessel stenosis, BBB permeability and inflammation. Remarkably, SBH/y-DOCA rats show severe white matter pathology as well as WMH, which are rarely reported in commonly used models.
Conclusions
Our model may serve as a novel platform for further understanding the mechanisms underlying CSVD and for discovery of novel therapies for this disease.