Alzheimer’s Disease: A Suitable Case for Treatment with Precision Medicine?

Medical Principles and Practice, Journal Year: 2024, Volume and Issue: 33(4), P. 301 - 309

Published: Jan. 1, 2024

Alzheimer’s disease (AD) is the most common cause of neurodegenerative impairment in elderly people. Clinical characteristics include short-term memory loss, confusion, hallucination, agitation, and behavioral disturbance. Owing to evolving research biomarkers, AD can be discovered at early onset, but currently considered a continuum, which suggests that pharmacotherapy efficacious preclinical phase, possibly 15–20 years before discernible onset. Present developments therapy aim respond this understanding go beyond drug families relieve clinical symptoms. Another important factor development emergence precision medicine aims tailor treatment specific patients or patient subgroups. This relatively new platform would categorize on basis parameters like aspects, brain imaging, genetic profiling, genetics, epidemiological factors. review enlarges recent progress design use antisense molecules, antibodies, antioxidants, small gene editing stop reverse relevant biomarkers.

Language: Английский

---

Role of Amyloidogenic and Non‐Amyloidogenic Protein Spaces in Neurodegenerative Diseases and their Mitigation Using Theranostic Agents

ChemBioChem, Journal Year: 2024, Volume and Issue: 25(13)

Published: April 26, 2024

Abstract Neurodegenerative diseases (NDDs) refer to a complex heterogeneous group of which are associated with the accumulation amyloid fibrils or plaques in brain leading progressive loss neuronal functions. Alzheimer's disease is one major NDD responsible for 60–80 % all dementia cases. Currently, there no curative disease‐reversing/modifying molecules many NDDs except few such as donepezil, rivastigmine, galantamine, carbidopa and levodopa treat disease‐associated symptoms. Similarly, very FDA‐approved tracers flortaucipir (Tauvid) tau fibril imaging florbetaben (Neuraceq), flutemetamol (Vizamyl), florbetapir (Amyvid) available diagnosis. Recent advances cryogenic electron microscopy reported distinctly different microstructures tauopathies highlighting possibility develop tauopathy‐specific agents therapeutics. In addition, it important identify proteins that development progression know about their 3D structure various diagnostics, therapeutics theranostic agents. The current article discusses detail non‐amyloid along structural insights. We comprehensively discussed novel implications pathology. we document emerging chemical compounds developed diagnosis therapy special emphasis on better management NDDs.

Language: Английский

---

APOE4 increases energy metabolism in APOE-isogenic iPSC-derived neurons

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 3, 2024

Abstract The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer’s disease (AD). In contrast, APOE2 is known to lower AD while APOE3 defined as neutral. APOE plays a prominent role in bioenergetic homeostasis of brain, and early-stage metabolic changes have been detected brains patients. Although primarily expressed by astrocytes neurons also shown source APOE. However, little about differential three isoforms neuronal energy homeostasis. this study, we generated pure human (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4 or carrying an APOE-knockout (KO) investigate isoform-specific effects on metabolism. We showed that endogenously produced enhanced mitochondrial ATP production iN but not corresponding iPS cell line. This effect neither correlated with expression levels fission fusion proteins, nor intracellular secreted APOE, which were similar cells. basal respiration APOE-KO strongly differed more closely resembled indicating gain-of-function mechanism rather than loss-of-function. Taken together, our findings isogenic reveal genotype-dependent neuron-specific regulation oxidative

Language: Английский

---

APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons

Cells, Journal Year: 2024, Volume and Issue: 13(14), P. 1207 - 1207

Published: July 17, 2024

The apolipoprotein E4 (

Language: Английский

---

Inflammasome-Inhibiting Nanoligomers Are Neuroprotective against Space-Induced Pathology in Healthy and Diseased Three-Dimensional Human Motor and Prefrontal Cortex Brain Organoids

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(16), P. 3009 - 3021

Published: July 31, 2024

The microgravity and space environment has been linked to deficits in neuromuscular cognitive capabilities, hypothesized occur due accelerated aging neurodegeneration space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk astronauts tourists actively investigated for development of appropriate countermeasures. However, such space-induced offers opportunity screening therapeutic targets lead molecules treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target (on Earth), validation, mitigation microgravity-induced using our Nanoligomer platform, onboard 43-day SpaceX CRS-29 mission International Space Station. First, comparing 3D healthy diseased prefrontal cortex (PFC, cognition) motor neuron (MN, function) organoids, assessed pathology biomarkers relevant Alzheimer's disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS). Both PFC MN organoids showed significantly enhanced space, as measured through biomarkers, when compared their respective Earth controls. Second, tested top two molecules, NI112 that targeted NF-κB NI113 IL-6. We observed these Nanoligomers mitigate AD, FTD, ALS like amyloid beta-42 (Aβ42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), others. Moreover, treatment brain did not appear cause any observable toxicity or safety issues organoid tissue, suggesting good tolerability at physiologically doses. Together, results significant potential both translation neuroprotective countermeasures safer travel demonstrate usefulness rapid, clinical translation. assert use drug may ultimately benefit millions patients suffering from debilitating diseases on Earth.

Language: Английский

---

On the Axonal Transport of Lipid Nanoparticles in Primary Hippocampal Neurons

Journal of Drug Delivery Science and Technology, Journal Year: 2024, Volume and Issue: unknown, P. 106282 - 106282

Published: Oct. 1, 2024

Language: Английский

---

Inflammasome-Inhibiting Nanoligomers are Neuroprotective Against Space-Induced Pathology in Healthy and Diseased 3D Human Motor and Pre-Frontal Cortex Brain Organoids

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 20, 2024

ABSTRACT Microgravity and space environment has been linked to deficits in neuromuscular cognitive capabilities, hypothesized occur due accelerated aging neurodegeneration space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk astronauts tourists, actively investigated for development of appropriate countermeasures. However, such space-induced offers opportunity screening therapeutic targets lead molecules treating neurodegenerative diseases. Here we show, a proof-of-concept high-throughput target (on Earth), validation, mitigation microgravity-induced using our Nanoligomer™ platform, onboard 43-day SpaceX CRS-29 mission International Space Station (ISS). First, comparing 3D healthy diseased pre-frontal cortex (PFC, cognition) motor neuron (MN, function) organoids, assessed pathology biomarkers relevant Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS). Both PFC MN organoids showed significantly enhanced space, as measured through disease biomarkers, when compared their respective Earth controls. Second, tested top two molecules, NI112 which targeted NF-κB, NI113 that IL-6. We observed these Nanoligomers mitigate AD, FTD, ALS like amyloid beta-42 (Aβ42), phosphorylated Tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), others. Moreover, Nanoligomer treatment brain did not appear cause any observable toxicity or safety issues organoid tissue, suggesting good tolerability at physiologically doses. Together, results show significant potential both translation neuroprotective countermeasures safer travel, demonstrate usefulness rapid, clinical translation. assert use microgravity drug may ultimately benefit millions patients suffering from debilitating diseases on Earth.

Language: Английский

---

Sex differences in the relationship between depression and Alzheimer’s disease—mechanisms, genetics, and therapeutic opportunities

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: June 5, 2024

Depression and Alzheimer’s disease (AD) are prevalent neuropsychiatric disorders with intriguing epidemiological overlaps. Their interrelation has recently garnered widespread attention. Empirical evidence indicates that depressive significantly contribute to AD risk, approximately a quarter of patients have comorbid major disorder, which underscores the bidirectional link between depression. A growing body substantiates pervasive sex differences in both depression: conditions exhibit higher incidence among women than men. However, available literature on this topic is somewhat fragmented, no comprehensive review delineates disparities depression–AD correlation. In review, we bridge these gaps by summarizing recent progress understanding sex-based mechanisms, genetics, therapeutic prospects for depression AD. Additionally, outline key challenges field, holding potential improving treatment precision efficacy tailored male female patients’ distinct needs.

Language: Английский

---

Learning context-aware, distributed gene representations in spatial transcriptomics with SpaCEX

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 10, 2024

Distributed gene representations are pivotal in data-driven genomic research, offering a structured way to understand the complexities of data and providing foundation for various analysis tasks. Current representation learning methods demand costly pretraining on heterogeneous transcriptomic corpora, making them less approachable prone over-generalization. For spatial transcriptomics (ST), there is plethora spot embeddings but serious lacking method generating from profiles. In response, we present SpaCEX, pioneer cost-effective self-supervised model that generates ST through exploiting “context” identified as spatially co-expressed groups. SpaCEX-generated (SGE) feature context-awareness, rich semantics, robustness cross-sample technical artifacts. Extensive real analyses reveal biological relevance SpaCEX-identified contexts validate functional relational semantics SGEs. We further develop suite SGE-based computational range key downstream objectives: identifying disease-associated genes gene-gene interactions, pinpointing with designated expression patterns, enhancing coverage FISH-based ST, detecting variable genes, improving clustering. results demonstrate these methods’ superior performance, thereby affirming potential SGEs facilitating analytical task. Significance Statement Spatial enables identification relationships within tissues, semantically “contexts” understanding interconnections among genes. SpaCEX marks first endeavor effectively harnesses yield biologically relevant distributed representations. These serve powerful tool greatly facilitate exploration genetic mechanisms behind phenotypes diseases, exemplified by their utility tasks biomedical including silico expanding low-throughput, high-resolution technologies, diverse patterns (co-expression, pattern, specific levels across tissue domains), domain discovery.

Language: Английский

---

Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 10, 2024

SUMMARY Sortilin ( SORT1 ) is a lipoprotein receptor that shows genome-wide association with hypercholesterolemia, explained by its ability to control hepatic output of lipoproteins. Remarkably, also Alzheimer disease (AD) and frontotemporal lobe dementia, the most prevalent forms age-related dementias. Yet, sortilin’s contribution human brain lipid metabolism health remains unclear. Using humanized mouse strains iPSC-based cell models homeostasis, we document sortilin mediates neuronal uptake polyunsaturated fatty acids carried apoE. Internalized lipids are converted into ligands for PPARα, inducing transcription profiles enable neurons use long-chain as metabolic fuel. This pathway works apoE3, but lost AD risk factor apoE4, which disrupts endocytic activity. We role in fuel choice neurons, possibly crucial when supply glucose limited, aging brain.

Language: Английский

---