Age-Related Cognitive Deficits and Neurotransmitters

This study aimed to investigate if ellagic acid has beneficial effects on cognitive deficits in middle-aged overweight individuals and to propose a possible mechanism. A total of 150 middle-aged male participants, including 76 normal-weight and 74 overweight men, aged between 45 to 55 years, were recruited for this study. Both normal-weight and overweight participants were administered either 50 mg ellagic acid or placebo cellulose daily for 12 weeks. Blood lipids, peripheral brain-derived neurotrophic factor (BDNF), and saliva cortisol were assessed on the last day of the procedure to investigate the effects induced by ellagic acid. The results revealed that ellagic acid treatment improved the levels of blood lipid metabolism with a 4.7% decline in total cholesterol, 7.3% decline in triglycerides, 26.5% increase in high-density lipoprotein, and 6.5% decline in low-density lipoprotein. Additionally, ellagic acid increased plasma BDNF by 21.2% in the overweight group and showed no effects on normal-weight participants. Moreover, the increased saliva cortisol level in overweight individuals was inhibited by 22.7% in a 12-week ellagic acid treatment. Also, compared with placebo, overweight individuals who consumed ellagic acid showed enhanced cognitive function as measured by the Wechsler Adult Intelligence Scale-Revised and the Montreal Cognitive Assessment. To the best of our knowledge, this is the first report showing that ellagic acid prevents cognitive deficits through normalization of lipid metabolism, increase in plasma BDNF level, and reduction of saliva cortisol concentration. These results indicate that ellagic acid has a potential to restore cognitive performance related to mild age-related declines.

Download Full-text

Tip60 protects against amyloid-β peptide-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegenerative progression

10.1101/2020.06.09.142885 ◽

2020 ◽

Author(s):

Haolin Zhang ◽

Bhanu Chandra Karisetty ◽

Akanksha Bhatnagar ◽

Ellen M. Armour ◽

Mariah Beaver ◽

...

Keyword(s):

Cell Death ◽

Cognitive Deficits ◽

Late Stage ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Neuronal Cell ◽

Amyloid Β Peptide ◽

Histone Deacetylase 2 ◽

Age Related ◽

Late Stages

ABSTRACTAlzheimer’s disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-β (Aβ) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to Aβ peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown. Here we profile Tip60 HAT/HDAC2 dynamics and transcriptome-wide changes across early and late stage AD pathology in the Drosophila brain produced solely by human amyloid-β42. We show that early Aβ42 induction leads to disruption of Tip60 HAT/HDAC2 balance during early neurodegenerative stages preceding Aβ plaque accumulation that persists into late AD stages. Correlative transcriptome-wide studies reveal alterations in biological processes we classified as transient (early-stage only), late-onset (late-stage only), and constant (both). Increasing Tip60 HAT levels in the Aβ42 fly brain protects against AD functional pathologies that include Aβ plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 protects against Aβ42-induced transcriptomic alterations via distinct mechanisms during early and late stages of neurodegeneration. Our findings reveal distinct modes of neuroepigenetic gene changes and Tip60 neuroprotection in early versus late stages in AD that can serve as early biomarkers for AD, and support the therapeutic potential of Tip60 over the course of AD progression.

Download Full-text

Systemic Inflammation Mediates Age-Related Cognitive Deficits

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2018.00236 ◽

2018 ◽

Vol 10 ◽

Cited By ~ 24

Author(s):

Tian Lin ◽

Gene A. Liu ◽

Eliany Perez ◽

Robert D. Rainer ◽

Marcelo Febo ◽

...

Keyword(s):

Systemic Inflammation ◽

Cognitive Deficits ◽

Age Related

Download Full-text

A MultiTEP platform-based epitope vaccine targeting the phosphatase activating domain (PAD) of tau: therapeutic efficacy in PS19 mice

Scientific Reports ◽

10.1038/s41598-019-51809-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Armine Hovakimyan ◽

Tatevik Antonyan ◽

Sepideh Kiani Shabestari ◽

Olga Svystun ◽

Gor Chailyan ◽

...

Keyword(s):

Cognitive Deficits ◽

Therapeutic Efficacy ◽

Cell Epitope ◽

Antibody Responses ◽

Age Related ◽

Promising Target ◽

B Cell Epitope ◽

Effective Reduction ◽

Phosphatase Activation ◽

Tau Polymerization

Abstract Pathological tau correlates well with cognitive impairments in Alzheimer’s disease (AD) patients and therefore represents a promising target for immunotherapy. Targeting an appropriate B cell epitope in pathological tau could in theory produce an effective reduction of pathology without disrupting the function of normal native tau. Recent data demonstrate that the N-terminal region of tau (aa 2-18), termed the “phosphatase activation domain (PAD)”, is hidden within native Tau in a ‘paperclip’-like conformation. Conversely, PAD is exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and tau polymerization. Thus, we hypothesized that anti-tau2-18 antibodies may safely and specifically reduce pathological tau and prevent further aggregation, which in turn would neutralize tau toxicity. Therefore, we evaluated the immunogenicity and therapeutic efficacy of our MultiTEP platform-based vaccine targeting tau2-18 formulated with AdvaxCpG adjuvant (AV-1980R/A) in PS19 tau transgenic mice. The AV-1980R/A induced extremely high antibody responses and the resulting sera recognized neurofibrillary tangles and plaque-associated dystrophic neurites in AD brain sections. In addition, under non-denaturing conditions AV-1980R/A sera preferentially recognized AD-associated tau. Importantly, vaccination also prevented age-related motor and cognitive deficits in PS19 mice and significantly reduced insoluble total and phosphorylated tau species. Taken together, these findings suggest that predominantly targeting misfolded tau with AV-1980R/A could represent an effective strategy for AD immunotherapy.

Download Full-text

Stroke Induces a BDNF-Dependent Improvement in Cognitive Flexibility in Aged Mice

Neural Plasticity ◽

10.1155/2019/1460890 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

Josh Houlton ◽

Lisa Y. Y. Zhou ◽

Deanna Barwick ◽

Emma K. Gowing ◽

Andrew N. Clarkson

Keyword(s):

Animal Model ◽

Cognitive Flexibility ◽

Cognitive Deficits ◽

Cox Regression ◽

Reversal Task ◽

Critical Window ◽

Aged Mice ◽

Sham Surgery ◽

Age Related ◽

Old Mice

Stroke remains a leading cause of disability worldwide. Recently, we have established an animal model of stroke that results in delayed impairment in spatial memory, allowing us to better investigate cognitive deficits. Young and aged brains show different recovery profiles after stroke; therefore, we assessed aged-related differences in poststroke cognition. As neurotrophic support diminishes with age, we also investigated the involvement of brain-derived neurotrophic factor (BDNF) in these differences. Young (3-6 months old) and aged (16-21 months old) mice were trained in operant touchscreen chambers to complete a visual pairwise discrimination (VD) task. Stroke or sham surgery was induced using the photothrombotic model to induce a bilateral prefrontal cortex stroke. Five days poststroke, an additional cohort of aged stroke animals were treated with intracerebral hydrogels loaded with the BDNF decoy, TrkB-Fc. Following treatment, animals underwent the reversal and rereversal task to identify stroke-induced cognitive deficits at days 17 and 37 poststroke, respectively. Assessment of sham animals using Cox regression and log-rank analyses showed aged mice exhibit an increased impairment on VD reversal and rereversal learning compared to young controls. Stroke to young mice revealed no impairment on either task. In contrast, stroke to aged mice facilitated a significant improvement in reversal learning, which was dampened in the presence of the BDNF decoy, TrkB-Fc. In addition, aged stroke control animals required significantly less consecutive days and correction trials to master the reversal task, relative to aged shams, an effect dampened by TrkB-Fc. Our findings support age-related differences in recovery of cognitive function after stroke. Interestingly, aged stroke animals outperformed their sham counterparts, suggesting reopening of a critical window for recovery that is being mediated by BDNF.

Download Full-text

Age-Related Decrease in Striatal DA Produces Cognitive Deficits in Male Rats

Journal of Pharmacy and Nutrition Sciences ◽

10.6000/1927-5951.2011.01.01.05 ◽

2011 ◽

pp. 20-27 ◽

Cited By ~ 14

Author(s):

Haider

Keyword(s):

Cognitive Deficits ◽

Male Rats ◽

Age Related

Download Full-text

Nerve growth factor reduces age-related functional cognitive deficits in rats: Correlation with biochemical forebrain cholinergic markers

Neurobiology of Aging ◽

10.1016/0197-4580(90)90935-s ◽

1990 ◽

Vol 11 (3) ◽

pp. 346

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Cognitive Deficits ◽

Nerve Growth ◽

Age Related ◽

Cholinergic Markers

Download Full-text

The combination of β-asarone and icariin inhibits amyloid-β and reverses cognitive deficits by promoting mitophagy in models of Alzheimer’s disease

10.21203/rs.3.rs-411952/v1 ◽

2021 ◽

Author(s):

Nanbu Wang ◽

Haoyu Wang ◽

Qi Pan ◽

Jian Kang ◽

Ziwen Liang ◽

...

Keyword(s):

Cognitive Deficits ◽

Pc12 Cell ◽

Cell Model ◽

Amyloid Β ◽

Beclin 1 ◽

Group Model ◽

Cell Models ◽

Age Related ◽

Transmission Electron ◽

Potential Strategy

Abstract Background: β-Asarone is the main constituent of Acorus tatarinowii Schott and exhibits important effects in diseases such as neurodegenerative and neurovascular diseases. Icariin (ICA) is a major active ingredient of Epimedium that has attracted increasing attention because of its unique pharmacological effects in degenerative disease. In this paper, we primarily explored the effects of the combination of β-asarone and ICA in clearing noxious proteins and reversing cognitive deficits. The accumulation of damaged mitochondria and mitophagy are characteristics of ageing and age-related neurodegeneration, including AD.Methods: APP/PS1 mice and in Aβ1-42-induced PC12 cell models were used. The groups were divided into five: normal group, model group (above animals and cells), icariin combined with β-asarone group, A3 and CSA group. Transmission electron microscopy was used to observe brain tissues (hippocampus and temporal lobe)/cell mitochondria, autophagosomes and other structures. IF and WB were used to detect the expression of Beclin-1, LC3, p62, Pink1, Parkin and p-Parkin. Dal-autophagy combined with LSCM was used to detect the occurrence of Autophagy. Mitophagy Detection Kit combined with LSCM was used to detect the occurrence of mitochondrial autophagy, and the effects of icariin combined with β-asarone on mitochondrial autophagy in AD animal and cell model were investigated.Results: We showed evidence that autophagy/mitophagy is damaged in the hippocampus of APP/PS1 mice and in Aβ1-42-induced PC12 cell models. Then, we found that the combination therapy can reduce the cytotoxicity caused by Aβ1-42, increase cell viability, inhibit the expression of Aβ, APP, PS1 and BACE1, and promote the expression of SYN. The efficacy of the combination is better than that of the single drug. What’s more, it also promoted the expression of Beclin-1, LC3 Ⅰ/ in, Pink1, Parkin and p-parkin while inhibited p62. Conclusion: These conclusions suggest that weakened removal of defective mitochondria is a pivotal event in AD pathogenesis and that combination treatment with mitophagy inducers represents a potential strategy for therapeutic intervention.

Download Full-text

Impulsivity in youth predicts early age-related cognitive deficits in rats

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2003.06.006 ◽

2004 ◽

Vol 25 (4) ◽

pp. 525-537 ◽

Cited By ~ 19

Author(s):

F Dellu-Hagedorn ◽

S Trunet ◽

H Simon

Keyword(s):

Cognitive Deficits ◽

Early Age ◽

Age Related

Download Full-text