Animal Models Of Alzheimer's Disease Research Articles

High-Fat Diets in Animal Models of Alzheimer's Disease: How Can Eating Too Much Fat Increase Alzheimer's Disease Risk?

High dietary intake of saturated fatty acids is a suspected risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To decipher the causal link behind these associations, high-fat diets (HFD) have been repeatedly investigated in animal models. Preclinical studies allow full control over dietary composition, avoiding ethical concerns in clinical trials. The goal of the present article is to provide a narrative review of reports on HFD in animal models of AD. Eligibility criteria included mouse models of AD fed a HFD defined as > 35% of fat/weight and western diets containing > 1% cholesterol or > 15% sugar. MEDLINE and Embase databases were searched from 1946 to August 2022, and 32 preclinical studies were included in the review. HFD-induced obesity and metabolic disturbances such as insulin resistance and glucose intolerance have been replicated in most studies, but with methodological variability. Most studies have found an aggravating effect of HFD on brain Aβ pathology, whereas tau pathology has been much less studied, and results are more equivocal. While most reports show HFD-induced impairment on cognitive behavior, confounding factors may blur their interpretation. In summary, despite conflicting results, exposing rodents to diets highly enriched in saturated fat induces not only metabolic defects, but also cognitive impairment often accompanied by aggravated neuropathological markers, most notably Aβ burden. Although there are important variations between methods, particularly the lack of diet characterization, these studies collectively suggest that excessive intake of saturated fat should be avoided in order to lower the incidence of AD.

Chronic intermittent hypoxia induces cognitive impairment in Alzheimer's disease mouse model via postsynaptic mechanisms.

Obstructive sleep apnea (OSA) is highly comorbid with Alzheimer's disease (AD) and may represent a risk factor for inducing or accelerating cognitive impairment in AD. Chronic intermittent hypoxia (CIH) has beenconsidered to be a predictor of developing cognitive decline and AD. However, the precise underlying mechanisms by which CIH contributes to cognitive impairment remain unknown. In the present study, we examined the effects of CIH on cognition and hippocampal function in APP/PS1 mice, an animal model of AD. Wild-type (WT) and APP/PS1 mice were subjected to one of the following conditions for 2weeks: (1) sham condition (continuous room air) or (2) CIH condition. The oxygen concentration of the CIH condition transitioned from 5 to 21%. Behavioral tests, electrophysiological recording, real-time polymerase chain reaction, and Western blot were used to assess the effect of CIHon cognitive performance and synaptic plasticity. CIH exposure did not affect motor coordination, general locomotor activity, anxiety, or willingnessto explore. However, behavioral test results indicated that APP/PS1-CIH mice showed more spatial learning and memory deficits. CIH induced long-term potentiation (LTP) dysfunction of thehippocampusin WT mice. These effects were aggravated in APP/PS1 mice. The N-methyl-D-aspartic acid receptor (NMDAR) NR1 subunit and postsynaptic density 95 (PSD95) in the hippocampus of WT and APP/PS1 mice were downregulated. These findings showed that a postsynaptic mechanism was involved in the effect of CIH on cognitive impairment.

Estradiol enhanced neuronal plasticity and ameliorated astrogliosis in human iPSC-derived neural models

Introduction17β-Estradiol (E2) is a sex hormone that has been previously demonstrated to have neurotherapeutic effects on animal models of Alzheimer's disease (AD). However, clinical trials on E2 replacement therapy for preventing AD onset yielded inconsistent results. Therefore, it is imperative to clarify the therapeutic effects of E2 on human cells. In this study, we utilized induced pluripotent stem cells (iPSCs) derived from multiple AD donors to explore the therapeutic effects of E2 on the in vitro model of human cells. MethodsWe conducted a systematic review and meta-analysis using a random-effects model of the previously reported AD clinical trials to summarize the effects of E2 replacement therapy on AD prevention. Subsequently, we induced iPSCs from the donors of the healthy control (1210B2 line (female) and 201B7 line (female)), the familial AD (APP V717L line (female) and APP KM670/671NL line (female)), and the sporadic AD (UCSD-SAD3.7 line (APOE ε3/ε3) (male), UCSD-SAD7D line (APOE ε3/ε4) (male), and TMGH-1 line (APOE ε3/ε3) (female)), then differentiated to neurons. In addition to the mono-culture model of the neurons, we also examined the effects of E2 on the co-culture model of neurons and astrocytes. ResultsThe meta-analysis of the clinical trials concluded that E2 replacement therapy reduced the risk of AD onset (OR, 0.69; 95 % confidence interval [CI], 0.53–0.91; I2 = 82 %). Neural models from the iPSCs of AD donors showed an increase in secreted amyloid-beta (Aβ) levels in the mono-culture model and an astrogliosis-like phenotype in the co-culture model. E2 treatment to the neuronal models derived from the iPSCs enhanced neuronal activity and increased neurite complexity. Furthermore, E2 treatment of the co-culture model ameliorated the astrogliosis-like phenotype. However, in contrast to the previous reports using mouse models, E2 treatment did not change AD pathogenesis, including Aβ secretion and phosphorylated tau (pTau) accumulation. ConclusionE2 treatment of the human cellular model did not impact Aβ secretion and pTau accumulation, but promoted neuronal plasticity and alleviated the astrogliosis-like phenotype. The limited effects of E2 may give a clue for the mixed results of E2 clinical trials.

A novel ferroptosis inhibitor, Thonningianin A, improves Alzheimer's disease by activating GPX4.

Background: Ferroptosis, a recently unveiled iron-dependent form of cellular demise, has emerged as a pivotal process contributing to the pathology of Alzheimer's Disease (AD). Glutathione Peroxidase 4 (GPX4), a vital defense mechanism countering ferroptosis by nullifying lipid peroxides and maintaining cellular redox equilibrium, has garnered significant attention in AD. Thus, identifying ferroptosis inhibitors to target GPX4 activation may help mitigate neuronal damage and impede AD progression. Objectives: We aimed to screen potent ferroptosis inhibitors and investigate their mechanism of action and therapeutic potential in AD, as well as lay the groundwork for future research in this promising area of study. Methods: This study employed a natural compound library to screen potential ferroptosis inhibitors in RAS-selective lethal compounds 3 (RSL-3)-induced PC-12 cells. Ferroptosis was evaluated by examining the mitochondrial morphology and function, reactive oxygen species (ROS) production, and lipid peroxide levels. The ability to chelate iron and intracellular iron levels was determined by UHPLC-Q/TOF-MS/MS and PGSK staining, respectively. APP Swe/ind- or Tau P301L-overexpressing PC-12 cells, and Amyloid-β transgenic CL4176 and Tau transgenic BR5270 Caenorhabditis elegans were employed as cellular and animal models of AD. Results: Thonningianin A (ThA) was identified as a novel ferroptosis inhibitor, as demonstrated by augmented cellular viability, mitigated mitochondrial impairment, diminished lipid peroxides, iron levels, and ROS generation. Mechanistically, ThA binds with GPX4 and enhances the AMPK/Nrf2 signaling pathway to stimulate GPX4 activation, effectively inhibiting ferroptosis. Moreover, in cellular and Caenorhabditis elegans AD models, ThA substantially inhibits ferroptosis by reducing ROS, lipid peroxide generation, and iron accumulation. Furthermore, ThA significantly delays paralysis, ameliorates food-sensing deficits and increases worms' antioxidative capacity. Conclusion: ThA ameliorates AD by inhibiting neuronal ferroptosis mediated by GPX4 activation through its binding with GPX4 and the upregulation of the AMPK/Nrf2/GPX4 pathway.

Effect of mesenchymal stem cells and polyvinyl alcohol-coated selenium nanoparticles on rats with Alzheimer-like phenotypes.

Mesenchymal stem cell (MSC) transplantation represents a promising approach for treating Alzheimer's disease (AD). These stem cells, however, have a short lifespan following transplantation into recipient animals. Selenium nanoparticles, due to their size, aid in drug delivery for brain disorders. This study investigated the therapeutic effect of MSCs and polyvinyl alcohol (PVA)-coated selenium nanoparticles (SeNPs) in a rat model of AD. An Alzheimer-like phenotype was induced through intracerebroventricular (ICV) administration of streptozotocin (STZ). Rats were assigned to five groups: control, Alz (STZ; 3 mg/kg, 10 μl, ICV), Alz+stem cell (ICV transplantation), Alz+SeNP (0.4 mg/kg, orally), and Alz+stem cell+SeNPs. The ICV administration of STZ mimicked some aspects of AD in the Alz groups. SeNPs were administrated for 30 days following STZ administration. The novel object recognition (NOR) and passive avoidance learning (PAL) tests were used to evaluate cognition and memory. Oxidative stress biomarkers and brain-derived neurotrophic factor (BDNF) were assessed by biochemical analysis, ELISA kits, and Congo red staining, respectively. The combined therapy of PVA-coated SeNPs and MSC transplantation was more effective in enhancing memory reacquisition compared to either SeNPs or MSCs alone. The use of stem cells in conjunction with PVA-coated SeNPs significantly boosted anti-oxidant capacity. The results suggest that the joint treatment with PVA-coated SeNPs and MSCs offers considerable neuroprotection against AD in animal models.

Testosterone deficiency worsens mitochondrial dysfunction in APP/PS1 mice.

Recent studies show testosterone (T) deficiency worsens cognitive impairment in Alzheimer's disease (AD) patients. Mitochondrial dysfunction, as an early event of AD, is becoming critical hallmark of AD pathogenesis. However, currently, whether T deficiency exacerbates mitochondrial dysfunction of men with AD remains unclear. The purpose of this study is to explore the effects of T deficiency on mitochondrial dysfunction of male AD mouse models and its potential mechanisms. Alzheimer's disease animal model with T deficiency was performed by castration to 3-month-old male APP/PS1 mice. Hippocampal mitochondrial function of mice was analyzed by spectrophotometry and flow cytometry. The gene expression levels related to mitochondrial biogenesis and mitochondrial dynamics were determined through quantitative real-time PCR (qPCR) and western blot analysis. SH-SY5Y cells treated with flutamide, T and/or H2O2 were processed for analyzing the potential mechanisms of T on mitochondrial dysfunction. Testosterone deficiency significantly aggravated the cognitive deficits and hippocampal pathologic damage of male APP/PS1 mice. These effects were consistent with exacerbated mitochondrial dysfunction by gonadectomy to male APP/PS1 mice, reflected by further increase in oxidative damage and decrease in mitochondrial membrane potential, complex IV activity and ATP levels. More importantly, T deficiency induced the exacerbation of compromised mitochondrial homeostasis in male APP/PS1 mice by exerting detrimental effects on mitochondrial biogenesis and mitochondrial dynamics at mRNA and protein level, leading to more defective mitochondria accumulated in the hippocampus. In vitro studies using SH-SY5Y cells validated T's protective effects on the H2O2-induced mitochondrial dysfunction, mitochondrial biogenesis impairment, and mitochondrial dynamics imbalance. Administering androgen receptor (AR) antagonist flutamide weakened the beneficial effects of T pretreatment on H2O2-treated SH-SY5Y cells, demonstrating a critical role of classical AR pathway in maintaining mitochondrial function. Testosterone deficiency exacerbates hippocampal mitochondrial dysfunction of male APP/PS1 mice by accumulating more defective mitochondria. Thus, appropriate T levels in the early stage of AD might be beneficial in delaying AD pathology by improving mitochondrial biogenesis and mitochondrial dynamics.

Alterations in mRNA level of proteins related to redox state and mitochondria in an Alzheimer's disease animal model: Promising targets in neuroprotection.

Oxidative stress and disturbances of mitochondrial function in the brain play a crucial role in Alzheimer's disease (AD). However, little is known about the dynamics of these changes in different parts of the brain at the early stage of AD. This study aimed to determine the expression of genes encoding superoxide dismutases (SOD1, SOD2), poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs). Moreover, transcription of genes related to mitochondrial electron transport complexes (ETC) and biogenesis in the brain cortex of 4-, 6- and 12-month-old transgenic AD Tg mice was analyzed. We observed significant decreases in mRNA of Sod2, Parp1 and Sirt1 in the 3-month-old AD Tg mice and upregulation of Parp1 in the 6-month-old AD Tg mice by qPCR analysis. Then, mt-CytB and mt-Co1 (complex III and IV) mRNA levels were increased in 12- and 6-month-old AD brains, respectively. These changes were linked to lower cytochrome c oxidase activity in 3- and significantly in 6-month-old AD Tg mice. Moreover, transcription of several genes involved in mitochondria biogenesis, such as Nfe2L2 and Tfam, was upregulated respectively in the 3- and 6-month-old AD Tg mice. Expression of genes encoding PGC1 and NRF2 was significantly downregulated in 12-month-old AD Tg mice. In summary, our data identified significant changes in gene expression of Sod2, Parp1 and Sirt1 at an early age (3-6-month-old AD mice) then Ppargc1, Nfe2L2 and Sirt1 at a later age. Recognizing these alterations may be important in better understanding the complexity of pathology in AD. Moreover, our results could be helpful in consideration of appropriate target(s) in neuroprotection.

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

Animal Models of Alzheimer's Disease: Current Strategies and New Directions

Animal Models of Alzheimer's Disease: Current Strategies and New Directions

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.

Stem cell factor restrains endoplasmic reticulum stress-associated apoptosis through c-Kit receptor activation of JAK2/STAT3 axis in hippocampal neuronal cells.

Alzheimer's disease (AD) is a common elderly disorder characterized by cognitive decline. Endoplasmic reticulum (ER) stress has been implicated in various neurodegenerative diseases, including AD. Stem cell factor (SCF) performs its biological functions by binding to and activating receptor tyrosine kinase c-Kit. We aimed to investigate the effects of SCF/c-Kit and JAK2/STAT3 on ER stress and apoptosis in AD. The study employed L-glutamic acid (L-Glu)-treated HT22 cells as sporadic AD cell model and APP/PS1 mice as an animal model of familiar AD. SCF, c-Kit inhibitor ISCK03 or JAK2/STAT3 inhibitor WP1066 was treated to verify the effects of SCF/c-Kit and JAK2/STAT3 on ER stress and apoptosis of L-Glu-exposed HT22 cells. Cell viability was assessed by MTT. BrdU detected cell proliferation. Flow cytometry measured cell apoptosis. The expression levels of ER stress markers GRP78, PERK, CHOP, and apoptosis protein caspase3 were determined by western blot. The effect on the mRNA of ER stress markers GRP78, PERK, CHOP and apoptotic caspase3 were quantified by RT-qPCR in primary cultured hippocampal neurons from APP/PS1 transgenic mice. Administration of SCF significantly augmented the activity and proliferation of hippocampal neuronal cells, protecting cells against L-Glu induced ER stress-associated apoptosis. Moreover, the addition of ISCK03 (c-Kit inhibitor) or WP1066 (JAK2/STAT3 inhibitor) reversed SCF effects on ER stress and apoptosis in vitro. We found that SCF inhibits L-Glu-induced ER stress-associated apoptosis via JAK2/STAT3 axis in HT22 hippocampal neuronal cells, as well as in primary hippocampal neurons from APP/PS1 mice, which provides valuable insights into the molecular mechanisms underlying the pathogenesis of AD and explores novel therapeutic targets for both sporadic and familial 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.