A genetically modified minipig model for Alzheimer’s disease with SORL1 haploinsufficiency

Andersen, Olav M.; Bøgh, Nikolaj; Landau, Anne M; Pløen, Gro Grunnet; Jensen, Anne Mette; Monti, Giulia; Ulhøi, Benedicte Parm; Nyengaard, Jens Randel; Jacobsen, Kirsten Rosenmay; Jørgensen, Margarita Melnikova; Holm, Ida E.; Kristensen, Marianne L; Alstrup, Aage Kristian Olsen; Hansen, Esben Szocska; Teunissen, Charlotte E.; Breidenbach, Laura; Droescher, Mathias; Liu, Ying; Pedersen, Helene Helboe; Callesen, Henrik; Luo, Yonglun; Bolund, Lars; Brooks, David J.; Laustsen, Christoffer; Small, Scott A.; Mikkelsen, Lars Friis; Sørensen, Charlotte Brandt

doi:10.1016/j.xcrm.2022.100740

Cited by 26 publications

(29 citation statements)

References 79 publications

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“…We also show that in addition to rescuing endo-lysosomal phenotypes, TPT-260 lowers Aβ and phosphorylated Tau (p-Tau) in all SORL1 conditions, suggesting that enhancing retromer can improve multiple cellular phenotypes in AD. Loss of one copy of SORL1 has been shown to be causative for AD(Andersen et al, 2022; Scheltens et al, 2021) and, in light of pathogenic variants in SORL1 that continue to be identified(Fazeli et al, 2023; Jensen AM, 2023), our data suggest that the SORL1 -retromer axis is important for future therapeutic development in AD.…”

Section: Introductionsupporting

confidence: 56%

Pharmacologic Stabilization of Retromer Rescues Endosomal Pathology Induced by Defects in the Alzheimer’s geneSORL1

Mishra

Knupp

Kinoshita

et al. 2022

Preprint

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Defects in the Sortilin-related receptor 1 gene, SORL1, are highly pathogenic in Alzheimer's disease (AD), on par with other causal AD genes. SORL1 is a key regulator of endosomal trafficking in neurons, and loss of SORL1 function disrupts trafficking pathways that are vital for neuronal health. SORL1 has been found to interact with retromer, a protein complex that is a 'master conductor' of endosomal trafficking. Here we rely on retromer pharmacological chaperones that stabilize retromer in vitro, and thus enhance retromer function in cells. to test the hypothesis that they will correct AD-associated neuronal pathologies. We used an isogenic series of human induced pluripotent stem cell (hiPSCs) lines either deficient in SORL1 expression (SORL1 KO or SORL1+/-) or harboring one copy of a missense variant linked to increased risk for AD (SORL1Var). We treated neurons derived from these hiPSCs with the established retromer chaperone, TPT-260, and tested whether they corrected indicators of AD's defining endosomal, amyloid, and Tau pathologies. We observed that TPT-260 treatment was able to correct all these pathological indicators; however, the degree of rescue of some of the phenotypes was dependent on whether the neurons harbor at least one functional copy of SORL1 or whether they are fully deficient. More than just validating that SORL1-retromer acts as a functional trafficking unit in neurons, our work sheds new light on how SORL1-retromer is linked to AD's cardinal pathologies and illuminates how this pathway can be therapeutically harnessed.

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Section: Introductionsupporting

confidence: 56%

Pharmacologic Stabilization of Retromer Rescues Endosomal Pathology Induced by Defects in the Alzheimer’s geneSORL1

Mishra

Knupp

Kinoshita

et al. 2022

Preprint

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“…A number of flavonoids have also been shown to have neuroprotective and neuroregenerative properties. Preclinical studies in rodent, pig, and monkey models of AD, PD, HD, and ALS [ 34 , 249 , 250 , 251 , 252 , 253 , 254 , 255 ] have also demonstrated that flavonoids have properties that counter neuroinflammation, prevent the neurotoxic effects of pathological protein aggregates of amyloid and hyperphosphorylated tau protein, free radical generation from peroxidation of lipids, and that brain tissues are rich in phospholipids that are susceptible to oxygen radical release during neuroinflammation. Some flavonoids act as monoamine oxidase inhibitors, combat apoptosis, are neuroprotective, promote neurogenesis and memory, and reduce cognitive decline [ 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 ].…”

Section: The Potential Of Flavonoids In Tissue Repair Processes In a ...mentioning

confidence: 99%

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

Melrose

2023

Antioxidants

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Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They have received considerable attention as potential therapeutic agents in biomedicine and have been widely used in traditional complimentary medicine for generations. Such complimentary medical herbal formulations are extremely complex mixtures of many pharmacologically active compounds that provide a therapeutic outcome through a network pharmacological effects of considerable complexity. Methods are emerging to determine the active components used in complimentary medicine and their therapeutic targets and to decipher the complexities of how network pharmacology provides such therapeutic effects. The gut microbiome has important roles to play in the generation of bioactive flavonoid metabolites retaining or exceeding the antioxidative and anti-inflammatory properties of the intact flavonoid and, in some cases, new antitumor and antineurodegenerative bioactivities. Certain food items have been identified with high prebiotic profiles suggesting that neutraceutical supplementation may be beneficially employed to preserve a healthy population of bacterial symbiont species and minimize the establishment of harmful pathogenic organisms. Gut health is an important consideration effecting the overall health and wellbeing of linked organ systems. Bioconversion of dietary flavonoid components in the gut generates therapeutic metabolites that can also be transported by the vagus nerve and systemic circulation to brain cell populations to exert a beneficial effect. This is particularly important in a number of neurological disorders (autism, bipolar disorder, AD, PD) characterized by effects on moods, resulting in depression and anxiety, impaired motor function, and long-term cognitive decline. Native flavonoids have many beneficial properties in the alleviation of inflammation in tissues, however, concerns have been raised that therapeutic levels of flavonoids may not be achieved, thus allowing them to display optimal therapeutic effects. Dietary manipulation and vagal stimulation have both yielded beneficial responses in the treatment of autism spectrum disorders, depression, and anxiety, establishing the vagal nerve as a route of communication in the gut-brain axis with established roles in disease intervention. While a number of native flavonoids are beneficial in the treatment of neurological disorders and are known to penetrate the blood–brain barrier, microbiome-generated flavonoid metabolites (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain the antioxidant and anti-inflammatory potency of the native flavonoid in addition to bioactive properties that promote mitochondrial health and cerebrovascular microcapillary function, should also be considered as potential biotherapeutic agents. Studies are warranted to experimentally examine the efficacy of flavonoid metabolites directly, as they emerge as novel therapeutic options.

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“…A knock out (KO) of SORL1 leads to ∼20 to ∼40% increase in secreted Aβ compared to WT in diverse cellular and animal models [50 ▪ ,51–53] with some diversity even among full KO models, while patients carry variants at the heterozygous state, with one exception [54]. Premature stop codon-introducing variants result in a LOF and are strongly enriched in patients, with odds ratios of no less than 27 [46].…”

Section: Looking For a Fourth Autosomal Dominant Gene: Novel Results ...mentioning

confidence: 99%

Recent advances in Alzheimer disease genetics

Nicolas

2024

Current Opinion in Neurology

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Purpose of review Genetics studies provide important insights into Alzheimer disease (AD) etiology and mechanisms. Critical advances have been made recently, mainly thanks to the access to novel techniques and larger studies. Recent findings In monogenic AD, progress has been made with a better understanding of the mechanisms associated with pathogenic variants and the input of clinical studies in presymptomatic individuals. In complex AD, increasing sample sizes in both DNA chip-based (genome-wide association studies, GWAS) and exome/genome sequencing case-control studies unveiled novel common and rare risk factors, while the understanding of their combined effect starts to suggest the existence of rare families with oligogenic inheritance of early-onset, nonmonogenic, AD. Summary Most genetic risk factors with a known consequence designate the aggregation of the Aβ peptide as a core etiological factor in complex AD thus confirming that the research based on monogenic AD – where the amyloid cascade seems more straightforward – is relevant to complex AD as well. Novel mechanistic insights and risk factor studies unveiling novel factors and attempting to combine the effect of common and rare variants will offer promising perspectives for future AD prevention, at least regarding early-onset AD, and probably in case of later onset as well.

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A genetically modified minipig model for Alzheimer’s disease with SORL1 haploinsufficiency

Cited by 26 publications

References 79 publications

Pharmacologic Stabilization of Retromer Rescues Endosomal Pathology Induced by Defects in the Alzheimer’s geneSORL1

Pharmacologic Stabilization of Retromer Rescues Endosomal Pathology Induced by Defects in the Alzheimer’s geneSORL1

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

Recent advances in Alzheimer disease genetics

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