scholarly journals In vivo testing of the role of Alzheimer’s disease coding variants

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Michael Sasner ◽  
Adrian L. Oblak ◽  
Dylan Garceau ◽  
Kevin P. Kotredes ◽  
Christoph Preuss ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vivo Testing ◽  
Coding Variants

[P2-409]: THE ROLE OF HIPPOCAMPAL SUBFIELDS IN THE ATROPHY PROCESS IN ALZHEIMER's DISEASE: AN IN-VIVO STUDY OF THE ADNI COHORT

2017 ◽  
Vol 13 (7S_Part_16) ◽  
pp. P788-P789
Author(s):  
Marzia Antonella Scelsi ◽  
Eugenio Iglesias ◽  
Jonathan M. Schott ◽  
Sebastien Ourselin ◽  
Andre Altmann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vivo Study ◽  
Hippocampal Subfields

scholarly journals TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading

2018 ◽  
Vol 215 (9) ◽  
pp. 2355-2377 ◽  
Author(s):  
Heidi Martini-Stoica ◽  
Allysa L. Cole ◽  
Daniel B. Swartzlander ◽  
Fading Chen ◽  
Ying-Wooi Wan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Connections ◽  
Transgenic Mouse Models ◽  
Reverse Effect ◽  
Tau Pathology ◽  
Transcription Factor Eb ◽  
Human Brains

The progression of tau pathology in Alzheimer’s disease follows a stereotyped pattern, and recent evidence suggests a role of synaptic connections in this process. Astrocytes are well positioned at the neuronal synapse to capture and degrade extracellular tau as it transits the synapse and hence could potentially have the ability to inhibit tau spreading and delay disease progression. Our study shows increased expression and activity of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, in response to tau pathology in both human brains with dementia and transgenic mouse models. Exogenous TFEB expression in primary astrocytes enhances tau fibril uptake and lysosomal activity, while TFEB knockout has the reverse effect. In vivo, induced TFEB expression in astrocytes reduces pathology in the hippocampus of PS19 tauopathy mice, as well as prominently attenuates tau spreading from the ipsilateral to the contralateral hippocampus in a mouse model of tau spreading. Our study suggests that astrocytic TFEB plays a functional role in modulating extracellular tau and the propagation of neuronal tau pathology in tauopathies such as Alzheimer’s disease.

[IC-P-047]: THE ROLE OF HIPPOCAMPAL SUBFIELDS IN THE ATROPHY PROCESS IN ALZHEIMER's DISEASE: AN IN-VIVO STUDY OF THE ADNI COHORT

2017 ◽  
Vol 13 (7S_Part_1) ◽  
pp. P40-P41 ◽  
Author(s):  
Marzia Antonella Scelsi ◽  
Eugenio Iglesias ◽  
Jonathan M. Schott ◽  
Sebastien Ourselin ◽  
Andre Altmann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vivo Study ◽  
Hippocampal Subfields

scholarly journals Repurposing Licensed Drugs for Use Against Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Leslie C. Norins
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Life Expectancy ◽  
Cost Effective ◽  
Epidemiological Data ◽  
Health Concern ◽  
Effective Manner ◽  
In Vivo Testing ◽  
Approved Drugs

Substantial evidence, composed of drug mechanisms of action, in vivo testing, and epidemiological data, exists to support clinical testing of FDA-approved drugs for repurposing to the treatment of Alzheimer’s disease (AD). Licensed compound investigation can often proceed at a faster and more cost-effective manner than un-approved compounds moving through the drug pipeline. As the prevalence of AD increases with life expectancy, the current rise in life expectancy amalgamated with the lack of an effective drug for the treatment of AD unnecessarily burdens our medical system and is an urgent public health concern. The unfounded reluctance to examine repurposing existing drugs for possible AD therapy further impedes the possibility of improving the quality of patient lives with a terminal disease. This review summarizes some evidence which exists to suggest certain already-approved drugs may be considered for the treatment of AD and will perhaps encourage physicians to off-label prescribe these safe therapeutics.

scholarly journals Lower MR-indexed locus coeruleus integrity in autosomal-dominant Alzheimer’s disease is related to cortical tau burden and memory deficits

2020 ◽  
Author(s):  
Martin J. Dahl ◽  
Mara Mather ◽  
Markus Werkle-Bergner ◽  
Briana L. Kennedy ◽  
Yuchuan Qiao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Resolution ◽  
Locus Coeruleus ◽  
Autosomal Dominant ◽  
Brain Regions ◽  
Cognitive Testing ◽  
Autosomal Dominant Alzheimer’S Disease

AbstractAbnormally phosphorylated tau, an indicator of Alzheimer’s disease, begins to accumulate in the first decades of life in the locus coeruleus (LC), the primary source of cortical norepinephrine. Ensuing dysfunction in noradrenergic neuromodulation is hypothesized to contribute to Alzheimer’s progression. However, research into the role of the LC has been impeded by a lack of effective ways of assessing it in vivo. Advances in high-resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s-related neuropathological markers in vivo.Leveraging a meta-analytical approach, we first synthesized LC localizations and dimensions across previously published studies to improve the reliability and validity of MR-based locus coeruleus detection. Next, we applied this refined volume of interest to determine whether MR-indexed LC integrity can serve as a marker for noradrenergic degeneration in early-onset Alzheimer’s disease. Eighteen participants (34.7±10.1 years; 9♀) with or known to be at-risk for mutations in genes associated with autosomal-dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T-MRI, flortaucipir positron emission tomography (PET), and cognitive testing. LC MRI intensity, a non-invasive proxy for neuronal density, was semi-automatically extracted from high-resolution brainstem scans across the rostrocaudal extent of the nucleus.Relative to healthy controls, symptomatic participants showed lower LC intensity. This effect was pronounced in rostral segments of the nucleus that project to the mediotemporal lobe and other memory-relevant areas. Among carriers of ADAD-causing mutations, closer proximity to the mutation-specific median age of dementia diagnosis was associated with lower LC intensity. Leveraging a multivariate statistical approach, we revealed a pattern of LC-related tau pathology in occipito-temporo-parietal brain regions. Finally, higher locus intensity was closely linked to memory performance across a variety of neuropsychological tests.Our finding of diminished MR-indexed LC integrity in autosomal-dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.

scholarly journals α-Synuclein modulates tau spreading in mouse brains

2020 ◽  
Vol 218 (1) ◽  
Author(s):  
Fares Bassil ◽  
Emily S. Meymand ◽  
Hannah J. Brown ◽  
Hong Xu ◽  
Timothy O. Cox ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Synergistic Effects ◽  
Tau Pathology ◽  
Vitro Data ◽  
In Vitro Data

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson’s disease (PD) and Alzheimer’s disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate–derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.

scholarly journals Synaptic Loss in Alzheimer's Disease: Mechanistic Insights Provided by Two-Photon in vivo Imaging of Transgenic Mouse Models

2020 ◽  
Vol 14 ◽  
Author(s):  
Jaichandar Subramanian ◽  
Julie C. Savage ◽  
Marie-Ève Tremblay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Synaptic Loss ◽  
Two Photon ◽  
Synapse Loss ◽  
Disease Mutations ◽  
The Brain

Synapse loss is the strongest correlate for cognitive decline in Alzheimer's disease. The mechanisms underlying synapse loss have been extensively investigated using mouse models expressing genes with human familial Alzheimer's disease mutations. In this review, we summarize how multiphoton in vivo imaging has improved our understanding of synapse loss mechanisms associated with excessive amyloid in the living animal brain. We also discuss evidence obtained from these imaging studies for the role of cell-intrinsic calcium dyshomeostasis and cell-extrinsic activities of microglia, which are the immune cells of the brain, in mediating synapse loss.

scholarly journals Copper Modulation as a Therapy for Alzheimer's Disease?

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Yasmina Manso ◽  
Gemma Comes ◽  
Juan Hidalgo ◽  
Ashley I. Bush ◽  
Paul A. Adlard
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Ion ◽  
Amyloid A ◽  
Animal Data ◽  
Clinical Literature ◽  
Behavioural Performance

The role of metals in the pathophysiology of Alzheimer's disease (AD) has gained considerable support in recent years, with both in vitro and in vivo data demonstrating that a mis-metabolism of metal ions, such as copper and zinc, may affect various cellular cascades that ultimately leads to the development and/or potentiation of AD. In this paper, we will provide an overview of the preclinical and clinical literature that specifically relates to attempts to affect the AD cascade by the modulation of brain copper levels. We will also detail our own novel animal data, where we treated APP/PS1 (7-8 months old) mice with either high copper (20 ppm in the drinking water), high cholesterol (2% supplement in the food) or a combination of both and then assessedβ-amyloid (Aβ) burden (soluble and insoluble Aβ), APP levels and behavioural performance in the Morris water maze. These data support an interaction between copper/cholesterol and both Aβand APP and further highlight the potential role of metal ion dyshomeostasis in AD.

scholarly journals Hormonal treatment, mild cognitive impairment and Alzheimer's disease

2008 ◽  
Vol 20 (1) ◽  
pp. 47-56 ◽  
Author(s):  
Joanne Ryan ◽  
Jaqueline Scali ◽  
Isabelle Carriere ◽  
Karen Ritchie ◽  
Marie-Laure Ancelin
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Verbal Memory ◽  
Late Onset ◽  
Controlled Trial ◽  
Hormonal Changes

ABSTRACTA plethora of in vitro and in vivo studies have supported the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented postmenopausal women suggest a temporary positive effect (notably on verbal memory), and four meta-analyses converge to suggest a possible protective effect in relation to Alzheimer's disease (reducing risk by 29 to 44%). However, data from the only large randomized controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Apart from methodological differences, one key shortcoming of this trial has probably been the focus on late-onset (postmenopausal) hormonal changes, i.e. at a time when the neurodegenerative process has already begun and without taking into account individual lifetime exposure to hormone variability. Multifactorial models based on an exhaustive view of all hormonal events throughout the reproductive life (rather than on a specific exposure to a given steroid) together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.

scholarly journals MicroRNAs and Alzheimer's Disease Mouse Models: Current Insights and Future Research Avenues

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Charlotte Delay ◽  
Sébastien S. Hébert
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Animal Models ◽  
Mouse Models ◽  
Future Research ◽  
Neuronal Function ◽  
Key Genes

Evidence from clinical trials as well as from studies performed in animal models suggest that both amyloid and tau pathologies function in concert with other factors to cause the severe neurodegeneration and dementia in Alzheimer’s disease (AD) patients. Accumulating data in the literature suggest that microRNAs (miRNAs) could be such factors. These conserved, small nonprotein-coding RNAs are essential for neuronal function and survival and have been implicated in the regulation of key genes involved in genetic and sporadic AD. The study of miRNA changes in AD mouse models provides an appealing approach to address the cause-consequence relationship between miRNA dysfunction and AD pathology in humans. Mouse models also provide attractive tools to validate miRNA targetsin vivoand provide unique platforms to study the role of specific miRNA-dependent gene pathways in disease. Finally, mouse models may be exploited for miRNA diagnostics in the fight against AD.

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