Animal Models Of Alzheimer's Disease Research Articles

Potential of Solanum betaceum to improve cognition: A systematic review of animal studies

Context: Solanum betaceum is rich in bioactive compounds associated with various health applications, including plausible benefits on cognitive impairment caused by neurodegenerative diseases such as Alzheimer’s disease (AD). Aims: To investigate the potential benefit of consuming S. betaceum to alleviate cognitive and memory decline. Methods: The review was conducted as a systematic review of an in vivo animal study. A search was performed of five databases using the keywords: “solanum betaceum”, “S. betaceum”, “tamarillo”, “neurodegenerative diseases”, “memory loss”, “cognitive impairment”. SYRCLE tool was used to assess the risk of bias. Data on the underlying molecular mechanisms of behavioral efficacy was additionally collected. Results: A total of 66 journals were retrieved from the databases, resulting in 3 eligible studies. All included studies used albino rats as an AD animal model that were accustomed to laboratory conditions for about a week prior to the disease induction. In two studies, aluminum chloride (AlCl3) was utilized to induce memory deficit, while another study used cigarette smoke. The result indicated that S. betaceum contained compounds such as phenolic and anthocyanin, which were plausibly responsible for the positive cognitive outcomes through molecular interaction with intracellular signaling protein cascades associated with anti-inflammation, brain oxygenation, synaptic plasticity, and cell viability. Further preclinical studies are needed to confirm these potentials. Conclusions: This systematic review of the current evidence on the behavioral and biological influences of S. betaceum administration on AD animal models pointed out that the fruit might improve cognitive performance and prevent cognitive deterioration raised by several neurotoxins.

Integrative medicinal approaches towards Alzheimer's disease model animals–A new hope

Integrative medicinal approaches towards Alzheimer's disease model animals–A new hope

ACOT7, a candidate and novel serum biomarker of Alzheimer's disease.

Alzheimer's disease (AD) is the most common fatal neurodegenerative disease among the elderly worldwide, characterized by memory and cognitive impairment. The identification of biomarkers for AD is crucial and urgent to facilitate the diagnosis and intervention. The aim of this study was to evaluate the diagnostic value of acyl-Coenzyme A thioesterase 7 (ACOT7) as a serum biomarker for the prediction of AD. In our study, we observed a significant increase in ACOT7 expression in patients (n = 366) with AD and animal (n = 8-12) models of AD, compared to the control group. A significant negative correlation was found between ACOT7 levels and Mini-Mental State Examination (MMSE) scores (r = -0.85; p < 0.001). The analysis of the receiver operating characteristic curve (ROC) showed that the area under the curve (AUC) for ACOT7 was 0.83 (95% confidence intervals: 0.80-0.86). The optimal cut-off point of 62.5 pg./mL was selected with the highest sum of sensitivity and specificity. The diagnostic accuracy of serum ACOT7 for AD was 77% (95% confidence intervals: 72-82%), with a sensitivity of 80% (95% confidence intervals: 75-84%) and a specificity of 74% (95% confidence intervals: 69-79%). Moreover, the ROC analysis showed that the AUC of Aβ42/40 ratio is 0.70, and the diagnostic accuracy was 72%, with 69% sensitivity and 76% specificity. Compared with the AD traditional marker Aβ42/40 ratio, ACOT7 shows better superiority as a new serum candidate biomarker of AD. By suppressing the ACOT7 gene, our study provides evidence of the involvement of ACOT7 in the metabolism of amyloid precursor protein (APP), resulting in alterations in the expression levels of Aβ42, BACE1 and βCTF. ACOT7 has the ability to modulate the amyloidogenic pathway of APP metabolism, while it does not have an impact on the non-amyloidogenic pathway. In conclusion, the findings of our study suggest that serum ACOT7 may serve as a promising and non-invasive biomarker for AD.

Alteration of Thyroid Hormones in Mouse Models of Alzheimer’s Disease and Aging

Plain Language SummaryIn order to prove the relationship between alteration of thyroid hormones (THs) and Alzheimer’s disease (AD), as well as aging, we established animal models of AD and naturally aging and performed thyroid function test and bulk RNA sequencing. We also studied gene perturbation correlation in AD mouse thyroid, bone marrow, and brain by further single-cell RNA sequencing (scRNA-seq) data of the bone marrow and brain. Our findings identified immune cell infiltration of the thyroid as the potential underlying mechanism of the alteration of THs in AD and aging.

Cacao Ameliorates Amyloid Beta-Induced Cognitive and Non-Cognitive Disturbances.

Alzheimer's disease (AD) is a progressive neurological disorder characterized by a wide range of cognitive and non-cognitive impairments. The present study was designed to investigate the potential effects of cacao on cognitive and non-cognitive performance and to identify the role of oxidative stress in an AD animal model induced by unilateral intracerebroventricular (U-ICV) injection of amyloid beta1-42 (Aβ1-42). Oral administration of cacao (0.5 g/kg/day) was performed for 60 consecutive days. Following 60 days, the open-field (OF) test, elevated plus-maze (EPM) test, novel object recognition (NOR) test, Barnes maze (BM) test, and Morris water maze (MWM) test were used to evaluate locomotor activity, anxiety-like behavior, recognition memory, and spatial memory, respectively. Total oxidant status (TOS) and total antioxidant capacity (TAC) in plasma were also examined. Furthermore, the number of healthy cells in the hippocampus's dentate gyrus (DG), CA1, and CA3 regions were identified using hematoxylin and eosin staining. The results indicated that the injection of Aβ1-42 in rats led to recognition memory and spatial memory impairments, as well as increased anxiety. This was accompanied by decreased total antioxidant capacity (TAC), increased total oxidative stress (TOS), and increased neuronal death. Conversely, cacao treatment in AD rats improved memory function, reduced anxiety, modulated oxidative stress balance, and decreased neuronal death. The findings suggest that cacao's ability to improve the balance between oxidants and antioxidants and prevent neuronal loss may be the mechanism underlying its beneficial effect against AD-related cognitive and non-cognitive impairments.

Cerebrovascular Dysfunction in Alzheimer's Disease and Transgenic Rodent Models.

Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementia (ADRD) are the primary causes of dementia that has a devastating effect on the quality of life and is a tremendous economic burden on the healthcare system. The accumulation of extracellular beta-amyloid (Aβ) plaques and intracellular hyperphosphorylated tau-containing neurofibrillary tangles (NFTs) in the brain are the hallmarks of AD. They are also thought to be the underlying cause of inflammation, neurodegeneration, brain atrophy, and cognitive impairments that accompany AD. The discovery of APP, PS1, and PS2 mutations that increase Aβ production in families with early onset familial AD led to the development of numerous transgenic rodent models of AD. These models have provided new insight into the role of Aβ in AD; however, they do not fully replicate AD pathology in patients. Familial AD patients with mutations that elevate the production of Aβ represent only a small fraction of dementia patients. In contrast, those with late-onset sporadic AD constitute the majority of cases. This observation, along with the failure of previous clinical trials targeting Aβ or Tau and the modest success of recent trials using Aβ monoclonal antibodies, has led to a reappraisal of the view that Aβ accumulation is the sole factor in the pathogenesis of AD. More recent studies have established that cerebral vascular dysfunction is one of the earliest changes seen in AD, and 67% of the candidate genes linked to AD are expressed in the cerebral vasculature. Thus, there is an increasing appreciation of the vascular contribution to AD, and the National Institute on Aging (NIA) and the Alzheimer's Disease Foundation recently prioritized it as a focused research area. This review summarizes the strengths and limitations of the most commonly used transgenic AD animal models and current views about the contribution of Aβ accumulation versus cerebrovascular dysfunction in the pathogenesis of AD.

Alleviation of behavioral deficits, amyloid-β deposition, and mitochondrial structure damage associated with mitophagy upregulation in AD animal models via AAV9-IGF-1 treatment

By safeguarding the neurological system, insulin-like growth factor 1 (IGF-1) may have a role in the etiology of Alzheimer's disease (AD). The mechanism and signaling route, however, remain unclear. This research aimed to investigate the impact of IGF-1 on AD as well as its possible mechanism and signaling route. In this work, intracerebroventricular AAV9-IGF-1 was delivered to APP/PS1 transgenic mice. Following therapy, the Morris water maze and passive avoidance tests were administered to evaluate spatial learning and memory. The elevated plus maze, the open field test, and the sucrose preference test were used to evaluate anxious-depressive-like behavior. Thioflavin S staining was employed to visualize Aβ deposition, and ELISA was used to determine the quantities of soluble Aβ1-40 and Aβ1-42. Transmission electron microscopy was used to view the mitochondrial structure and mitophagy vesicles. The protein expression levels of PINK1, Parkin, and LC3-II/LC3-I were finally determined by Western blotting. AAV9-IGF-1 therapy enhanced spatial learning and memory, relieved anxious-depressive-like behavior impairments, lowered amyloid-β deposition, and decreased levels of soluble Aβ1-40 and Aβ1-42. In addition, AAV9-IGF-1 therapy restored mitochondrial integrity and increased the number of mitophagy in transgenic mice expressing APP/PS1. These results indicate that IGF-1 is protective for APP/PS1 mice. The mechanism of the favorable benefits mediated by IGF-1 was connected to an increase in mitophagy, which might give a novel therapy target in the future.

Tau seeds from Alzheimer's disease brains trigger tau spread in macaques while oligomeric-Aβ mediates pathology maturation.

The "prion-like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid-β (Aβ) have never been experimentally studied in primates phylogenetically close to humans. We injected 17 macaques in the entorhinal cortex with nanograms of seeding-competent tau aggregates purified from AD brains or control extracts from aged-matched healthy brains, with or without intracerebroventricular co-injections of oligomeric-Aβ. Pathological tau injection increased cerebrospinal fluid (CSF) p-tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD-related molecular networks were impacted by tau seeds injections regardless of Aβ injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total-tau concentration, and pre- and postsynaptic degeneration only in Aβ co-injected macaques. Oligomeric-Aβ mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading. This study supports the "prion-like" properties of misfolded tau extracted from AD brains. This study empirically validates the Braak staging in an anthropomorphic brain. This study highlights the role of oligomeric Aβ in driving the maturation and toxicity of tau pathology. This work establishes a novel animal model of early sporadic AD that is closer to the human pathology.

Beneficial Fruit-Derived Phytochemicals in Treating Alzheimer’s Disease – A Review

Fruits, as a major source of nutrition have been investigated for their emerging evidence of several neuroprotective activities beneficial to Alzheimer’s disease (AD). This paper discusses recent evidence suggesting several fruit-derived bioactive substances that possess anti-AD activity. The original articles from 2011–2022 were collected from Pubmed and Scopus with related keywords and filtered. Several fruit constituents have shown significant inhibitory action against β-amyloid and tau hyperphosphorylation, either directly or indirectly via secretase inhibition. Some were also found to be cholinesterase inhibitors with specific antioxidative roles, disruptors of the neuroinflammation system, and promoters of neurogenesis and the neurogenic process. Many fruit phytochemicals remarkably alter the capability defects shown in AD animal models, such as catechin, nobiletin, and alpha-mangostin. Therefore, further investigations exploring a certain bioactive isolate or formulated dosage form and its mechanism of action are necessary to provide effective prevention and supplementary treatment for AD.

Dentate Gyrus Granule Cells Show Stability of BDNF Protein Expression in Mossy Fiber Axons with Age, and Resistance to Alzheimer's Disease Neuropathology in a Mouse Model.

Brain-derived neurotrophic factor (BDNF) is important in the development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and not in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild-type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either the genotype or sex. Notably, MF BDNF protein was correlated with GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. We also report the novel finding that Aβ in GCs or the GC layer was minimal even at old ages. The results indicate that MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect vulnerable neurons from increased Aβ levels and therefore has translational implications.

Switching On/Off Amyloid Plaque Formation in Transgenic Animal Models of Alzheimer's Disease.

A hallmark of Alzheimer's disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aβ) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aβ may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis, any agent that has the capability to inhibit Aβ aggregation and/or destroy amyloid plaques represents a potential disease-modifying drug. In 2023, a humanized IgG1 monoclonal antibody (lecanemab) against the Aβ-soluble protofibrils was approved by the US FDA for AD therapy, thus providing compelling support to the amyloid hypothesis. To acquire a deeper insight on the in vivo Aβ aggregation, various animal models, including aged herbivores and carnivores, non-human primates, transgenic rodents, fish and worms were widely exploited. This review is based on the recent data obtained using transgenic animal AD models and presents experimental verification of the critical role in Aβ aggregation seeding of the interactions between zinc ions, Aβ with the isomerized Asp7 (isoD7-Aβ) and the α4β2 nicotinic acetylcholine receptor.

Amyloid-β specific regulatory T cells attenuate Alzheimer’s disease pathobiology in APP/PS1 mice

BackgroundRegulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions is required for disease-specific therapeutic targeting and improved outcomes. To address this need, amyloid-beta (Aβ) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for Aβ (TCRAβ). The TCRAb were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCRAβ (TCRAβ -Tregs) to reduce Aβ burden, transform effector to regulatory cells, and reverse disease-associated neurotoxicity proved beneficial in an animal model of Alzheimer’s disease.MethodsTCRAβ -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCRAb identified from Aβ reactive Teff monoclones. Antigen specificity was confirmed by MHC-Aβ-tetramer staining. Adoptive transfer of TCRAβ-Tregs to mice expressing a chimeric mouse-human amyloid precursor protein and a mutant human presenilin-1 followed measured behavior, immune, and immunohistochemical outcomes.ResultsTCRAβ-Tregs expressed an Aβ-specific TCR. Adoptive transfer of TCRAβ-Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. 18F-fluorodeoxyglucose radiolabeled TCRAβ-Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions.ConclusionsTCRAβ-Tregs reduced amyloid burden, restored brain homeostasis, and improved learning and memory, supporting the increased therapeutic benefit of antigen specific Treg immunotherapy for AD.Graphical

Human neural stem cells restore spatial memory in a transgenic Alzheimer's disease mouse model by an immunomodulating mechanism.

Stem cells are a promising therapeutic in Alzheimer's disease (AD) given the complex pathophysiologic pathways involved. However, the therapeutic mechanisms of stem cells remain unclear. Here, we used spatial transcriptomics to elucidate therapeutic mechanisms of human neural stem cells (hNSCs) in an animal model of AD. hNSCs were transplanted into the fimbria fornix of the hippocampus using the 5XFAD mouse model. Spatial memory was assessed by Morris water maze. Amyloid plaque burden was quantified. Spatial transcriptomics was performed and differentially expressed genes (DEGs) identified both globally and within the hippocampus. Subsequent pathway enrichment and ligand-receptor network analysis was performed. hNSC transplantation restored learning curves of 5XFAD mice. However, there were no changes in amyloid plaque burden. Spatial transcriptomics showed 1,061 DEGs normalized in hippocampal subregions. Plaque induced genes in microglia, along with populations of stage 1 and stage 2 disease associated microglia (DAM), were normalized upon hNSC transplantation. Pathologic signaling between hippocampus and DAM was also restored. hNSCs normalized many dysregulated genes, although this was not mediated by a change in amyloid plaque levels. Rather, hNSCs appear to exert beneficial effects in part by modulating microglia-mediated neuroinflammation and signaling in AD.

Effect and Potential Mechanism of Immunotherapy on Cognitive Deficits in Animal Models of Alzheimer's Disease: A Systematic Review and Meta-Analysis

Immunotherapy has been reported to ameliorate Alzheimer's disease (AD) in the animal model; however, the immunologic approaches and mechanisms have not been specifically described. Thus, the systematic review and meta-analysis were conducted to explore the effect and potential mechanism of immunotherapy on AD animal experiments based on behavioral indicators. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Cochrane Collaboration guidelines and the inclusion/exclusion criteria of immunotherapy in animal studies, 15 studies were systematically reviewed after extraction from a collected database of 3,742 publications. Finally, the effect and mechanism of immunotherapy on AD models were described by performing multiple subgroup analyses. After immunotherapy, the escape latency was reduced by 18.15 seconds and the number of crossings over the platform location was increased by 1.60 times in the Morris Water Maze. Furthermore, compared to the control group, active and passive immunization could markedly ameliorate learning and memory impairment in 3 × Tg AD animal models, and active immunization could ameliorate the learning and memory ability of the APPswe/PS1ΔE9 AD animal model. Meanwhile, it could be speculated that cognitive dysfunction was improved by immunotherapy, perhaps mainly via reducing Aβ40, Aβ42, and Tau levels, as well as increasing IL-4 levels. Immunotherapy significantly ameliorated the cognitive dysfunction of AD animal models by assessing behavioral indicators.

TMT-based quantitative proteomics analysis of neuroprotective effects of Forsythoside A on the MPTP-induced Parkinson's disease mouse model

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characteristized by the presence of dyskinesia and the progressive loss of dopaminergic neurons. Although certain drugs can mitigate the symptoms of PD, they are unable to delay the disease progression, and their prolonged use may result in complications. Therefore, there exists an urgent necessity to identify potential agents that can effectively delay PD progression with fewer side effects. Recent research has unveiled that several traditional Chinese medicines (TCM) exhibit neuroprotective properties in various models pertinent to PD. Forsythoside A (FSA), the primary bioactive compound derived from TCM Lianqiao, has undergone extensive research in animal models of Alzheimer's disease and cerebral ischemia. However, the investigation into the impact of FSA on PD is limited in existing research. In this study, we aimed to evaluate the neuroprotective effects of FSA on MPTP-induced PD mouse model. FSA demonstrated significant improvements in the behavioral and neuropathological changes triggered by MPTP in mice. Furthermore, it exerted a suppressive effect on the activations of astrocyte and microglia. Meanwhile, Tandem mass tag (TMT)-based quantitative proteomics of striatal tissue and bioinformatics analysis were performed to elucidate the underlying mechanisms of FSA on PD mouse model. Proteomics demonstrated a total of 68 differentially expressed proteins (DEPs) were identified between HFSA and MPTP groups including 26 upregulated and 42 downregulated. Systematic bioinformatics analysis of the 68 DEPs illustrated that they were predominantly related to estrogen signaling pathway and calcium signaling pathway. The related DEPs (PLCβ4, Grm2, HPAC and Cox4i1) expression levels were verified by Western blot. FSA effectively restored the altered expression of the four DEPs induced by MPTP. Summarily, FSA exerted remarkable neuroprotective effects in MPTP-induced mice. Further, our research may provide proteomics insights that contribute to the further exploration of FSA as a potential treatment for PD.

Neuroprotective Profile of Triazole Grandisin Analogue against Amyloid-Beta Oligomer-Induced Cognitive Impairment.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-β oligomers (AβO) in the brain, neuroinflammation, oxidative stress, and cognitive decline. Grandisin, a tetrahydrofuran neolignan, exhibits relevant anti-inflammatory and antioxidant properties. Interestingly, grandisin-based compounds were shown to prevent AβO-induced neuronal death in vitro. However, no study has assessed the effect of these compounds on the AD animal model. This study focuses on a triazole grandisin analogue (TGA) synthesized using simplification and bioisosteric drug design, which resulted in improved potency and solubility compared with the parent compound. This study aimed to investigate the possible in vivo effects of TGA against AβO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AβO (90 μM) or vehicle injections. 24 h after surgery, animals received intraperitoneal treatment with TGA (1 mg/kg) or vehicle, administered on a 14 day schedule. One day after treatment completion, a novel object recognition task (NORT) was performed. Memantine (10 mg/kg) was administered as a positive control. NORT retention sessions were performed on days 8 and 16 after AβO injection. Immediately after retention sessions, animals were euthanized for cortex and hippocampus collection. Specimens were subjected to oxidative stress and cytokine analyses. TGA reduced the level of cortex/hippocampus lipoperoxidation and prevented cognitive impairment in AβO-injected mice. Additionally, TGA reduced tumor necrosis factor (TNF) and interferon-γ (IFN-γ) levels in the hippocampus. By contrast, memantine failed to prevent cortex/hippocampus lipid peroxidation, recognition memory decline, and AβO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AβO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AβO-injected mice. Moreover, TGA exhibited a persistent neuroprotective effect compared to memantine, reflecting an innovative profile of this promising agent against neurodegenerative diseases, such as AD.

AlzPED: Raising the Standards for Preclinical Efficacy Testing of Candidate Therapeutics in Alzheimer’s Disease

AbstractBackgroundPositive findings of therapeutics and interventions from studies conducted in Alzheimer’s disease (AD) animal models are often not translated to effective treatments. Assessments of these studies highlight the lack of methodological rigor and inadequate reporting practices as contributive to the preclinical to clinical translation gap in AD therapy development. AlzPED/Alzheimer’s Disease Preclinical Efficacy Database, developed by the NIA, is a searchable and publicly available knowledgebase that prioritizes and promotes the use of rigorous methodology in the planning of animal studies through its Rigor Report Card. The Rigor Report Card, through its checklist of experimental design elements, creates awareness of reporting recommendations and standards early in the research process and provides a practical and easy approach to planning a therapeutic study in animals.MethodUsing key word‐driven literature searches published studies are acquired and curated by two experts for bibliographic details, funding source, study goals and principal findings, data on relevant translational criteria like therapy type, therapeutic agent, therapeutic target, animal models, and AD‐related outcome measures, prior to publication in the database. Rigor in study design and methodology is evaluated with the Rigor Report Card.ResultAlzPED hosts curated summaries from nearly 1300 published preclinical therapeutic studies in AD animal models, and data related to 251 therapeutic targets, 1123 therapeutic agents, 210 animal models, more than 2000 AD‐related outcome measures, and thousands of principal findings. Evaluation of Rigor Report Cards from each study demonstrates significant under‐reporting of critical elements of methodology such as power/sample size calculation, blinding, randomization, balancing for sex, animal genetic background, and inclusion/exclusion criteria, these being reported by fewer than 35% of the nearly 1300 curated studies. These serious deficiencies in reporting critical elements of methodology diminish the scientific rigor, reproducibility, and translational value of the preclinical studies.ConclusionRigorous experimental design and transparent reporting are clearly essential if animal studies are to inform future research, science policies, and successful clinical trials. Adopting a standardized set of best practices like those proposed by AlzPED can improve the predictive power of preclinical studies in AD animal models and promote the effective translation of preclinical drug testing data to the clinic.

Brain catecholaminergic neurons control monocytes deployment to sites of injury and their loss exacerbate cognitive deterioration in an animal model of Alzheimer’s Disease

AbstractBackgroundThe CNS constantly monitors the organism’s internal state and orchestrates adaptive responses to perturbation of the body’s homeostasis. Emerging evidence revealed that the brain can also instruct immune responses, which in turn can affect the condition of other organs, including the brain itself.MethodWe used neuronal retrograde‐labelling, flow‐cytometry, mass cytometry, scRNAseq and cognitive tests in animal model of Alzheimer’s disease (5xFAD) to study the relevance of the brain Brain‐Immune axis in the context of Alzheimer’s Disease.ResultsWe found that catecholaminergic neurons are in direct communication with the spleen, the major secondary lymphoid organ of our body. This connection is impaired in an animal model of neurodegeneration (Alzheimer’s Disease ‐ AD), and undermining this communication at early stage of the disease accelerated disease manifestation. We found that monocytes are the most sensitive cell type to noradrenaline released by the splenic nerve and halting neuronal inputs to the spleen impairs monocytes’ migratory capacity. Monocytes are needed to cope with neurodegenerative diseases and acute CNS damage. Upon splenic denervation, we observed reduced number of monocytes in the brain of AD mice and impaired microglia maturation. Upon denervation of the spleen, reduced number of infiltrating monocytes was also observed in a model of retina excitotoxic damage.ConclusionsThese results highlight a novel pathway through which the CNS can control immune function and therefore trigger tissue repairing processes.

Mitophagy biomarkers are changed in the continuum of Alzheimer’s disease

AbstractBackgroundAutophagy is a cellular self “garbage clearance ”system through which cells eliminate and recycle dysfunctional cytoplasmatic components, such as defective organelles and misfolded protein aggregates. Mitophagy is the sub‐type of autophagy that recognizes and degrades damaged or superfluous mitochondria to maintain cellular homeostasis. Emerging evidence demonstrates that autophagy and mitophagy are impaired in Alzheimer’s disease (AD); its upregulation ameliorates Aß pathology and slows down the cognitive decline in animal models of AD, thus representing a potentially treatable target. The change in the mitophagy biomarkers in individuals with AD needs to be clarified. We aimed to explore the changes of mitophagy biomarkers in biomarkers‐defined individuals in various stages of AD and compare them to cognitively unimpaired individuals (CU).MethodWe included 228 biomarker‐defined individuals from the Czech Brain Aging Study:98 AD dementia (ADD), 88 mild cognitive impairment due to AD (MCI‐AD), and 42 CU individuals. They underwent clinical examination, complex neuropsychological assessment, and brain MRI. Commercial ELISA kits were used to measure standard AD biomarkers in CSF (Aß42, Aß40, pTau, tTau), a biomarker of neurodegeneration (neurofilament light chain – NfL), synaptic dysfunction (neurogranin, Ng), and mitophagy biomarkers in CSF (PINK1‐ mitochondrial kinase crucial for mitophagy) and in serum (BNIP3L‐ mitophagy receptor, TFEB‐ transcription factor critical for lysosomal degradation).ResultWe found a significant increase in PINK1 CSF and BNIP3L serum levels in ADD compared to MCI‐AD and CU (ps&lt;.001). TFEB serum levels were decreased in ADD compared to MCI‐AD and CU (ps&lt;.05). Additionally, in ADD, PINK1 correlated with NfL (r = 0.27) and Ng (r = 0.47). In MCI‐AD, there was a correlation between PINK1 and Ng (r = 0.51), but not with NfL. There was no correlation in CU individuals with NfL or Ng.ConclusionWe identified candidate proteins of mitophagy that are changed in various cognitive stages of AD. In the ADD stage, there is an upregulation of the mitophagy inducers, PINK1 and BNIP3L, together with decreased levels of TFEB, a master regulator of lysosomal biogenesis. One of the possible explanations is that these findings reflect impairment in the final stage of autophagy–lysosomal degradation. Further research is needed to clarify its pathophysiological importance in the AD cascade.

Tpr Misregulation in Hippocampal Neural Stem Cells in Mouse Models of Alzheimer's Disease.

Nuclear pore complexes (NPCs) are highly dynamic macromolecular protein structures that facilitate molecular exchange across the nuclear envelope. Aberrant NPC functioning has been implicated in neurodegeneration. The translocated promoter region (Tpr) is a critical scaffolding nucleoporin (Nup) of the nuclear basket, facing the interior of the NPC. However, the role of Tpr in adult neural stem/precursor cells (NSPCs) in Alzheimer's disease (AD) is unknown. Using super-resolution (SR) and electron microscopy, we defined the different subcellular localizations of Tpr and phospho-Tpr (P-Tpr) in NSPCs in vitro and in vivo. Elevated Tpr expression and reduced P-Tpr nuclear localization accompany NSPC differentiation along the neurogenic lineage. In 5xFAD mice, an animal model of AD, increased Tpr expression in DCX+ hippocampal neuroblasts precedes increased neurogenesis at an early stage, before the onset of amyloid-β plaque formation. Whereas nuclear basket Tpr interacts with chromatin modifiers and NSPC-related transcription factors, P-Tpr interacts and co-localizes with cyclin-dependent kinase 1 (Cdk1) at the nuclear chromatin of NSPCs. In hippocampal NSPCs in a mouse model of AD, aberrant Tpr expression was correlated with altered NPC morphology and counts, and Tpr was aberrantly expressed in postmortem human brain samples from patients with AD. Thus, we propose that altered levels and subcellular localization of Tpr in CNS disease affect Tpr functionality, which in turn regulates the architecture and number of NSPC NPCs, possibly leading to aberrant neurogenesis.