Differential loss of synaptic proteins in Alzheimer's disease: Implications for synaptic dysfunction

Synaptic loss and dysfunction are one of the earliest signs of neurodegeneration associated with cognitive decline in Alzheimer’s disease (AD). It seems that by assessing proteins related to synapses, one may reflect their dysfunction and improve the understanding of neurobiological processes in the early stage of the disease. To our best knowledge, this is the first study that analyzes the CSF concentrations of two synaptic proteins together, such as neurogranin (Ng) and neuronal pentraxins receptor (NPTXR) in relation to neurochemical dementia biomarkers in Alzheimer’s disease. Methods: Ng, NPTXR and classical AD biomarkers concentrations were measured in the CSF of patients with AD and non-demented controls (CTRL) using an enzyme-linked immunosorbent assay (ELISA) and Luminex xMAP technology. Results: The CSF level of Ng was significantly higher, whereas the NPTXR was significantly lower in the AD patients than in cognitively healthy controls. As a first, we calculated the NPTXR/Ng ratio as an indicator of synaptic disturbance. The patients with AD presented a significantly decreased NPTXR/Ng ratio. The correlation was observed between both proteins in the AD and the whole study group. Furthermore, the relationship between the Ng level and pTau181 was found in the AD group of patients. Conclusions: The Ng and NPTXR concentrations in CSF are promising synaptic dysfunction biomarkers reflecting pathological changes in AD.

Download Full-text

Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction

Journal of Alzheimer s Disease ◽

10.3233/jad-201599 ◽

2021 ◽

pp. 1-16

Author(s):

Wei Wei ◽

Yinghua Liu ◽

Chunling Dai ◽

Narjes Baazaoui ◽

Yunn-Chyn Tung ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Synaptic Plasticity ◽

Cognitive Function ◽

Early Development ◽

Neurodegenerative Disorder ◽

Synaptic Dysfunction ◽

Early Postnatal Development ◽

Wild Type Female

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Cognitive dysfunction and loss of neuronal plasticity are known to begin decades before the clinical diagnosis of the disease. The important influence of congenital genetic mutations on the early development of AD provides a novel opportunity to initiate treatment during early development to prevent the Alzheimer-like behavior and synaptic dysfunction. Objective: To explore strategies for early intervention to prevent Alzheimer’s disease. Methods: In the present study, we investigated the effect of treatment during early development with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGLAG-NH2) on cognitive function and synaptic plasticity in 3xTg-AD transgenic mouse model of AD. 3xTg-AD and genetic background-matched wild type female mice were treated from birth to postnatal day 120 with P021 in diet or as a control with vehicle diet, and cognitive function and molecular markers of neuroplasticity were evaluated. Results: P021 treatment during early development prevented cognitive impairment and increased expressions of pCREB and BDNF that activated downstream various signaling cascades such as PLC/PKC, MEK/ERK and PI3K/Akt, and ameliorated synaptic protein deficit in 4-month-old 3xTg-AD mice. Conclusion: These findings indicate that treatment with the neurotrophic peptide mimetic such as P021 during early development can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial AD and related tauopathies.

Download Full-text

A γ-adducin cleavage fragment induces neurite deficits and synaptic dysfunction in Alzheimer’s disease

Progress in Neurobiology ◽

10.1016/j.pneurobio.2021.102074 ◽

2021 ◽

pp. 102074

Author(s):

Min Xiong ◽

Li Zou ◽

Lanxia Meng ◽

Xingyu Zhang ◽

Ye Tian ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Dysfunction ◽

Cleavage Fragment

Download Full-text

Astrocytes and neuroinflammation in Alzheimer's disease

Biochemical Society Transactions ◽

10.1042/bst20140155 ◽

2014 ◽

Vol 42 (5) ◽

pp. 1321-1325 ◽

Cited By ~ 47

Author(s):

Emma C. Phillips ◽

Cara L. Croft ◽

Ksenia Kurbatskaya ◽

Michael J. O’Neill ◽

Michael L. Hutton ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Inflammatory Responses ◽

Amyloid Β ◽

Synaptic Dysfunction ◽

Amyloid Β Peptide ◽

Substantial Evidence ◽

Models Of Disease ◽

Opposing Effects

Increased production of amyloid β-peptide (Aβ) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases.

Download Full-text

E22Δ Mutation in Amyloidβ-Protein Promotesβ-Sheet Transformation, Radical Production, and Synaptotoxicity, But Not Neurotoxicity

International Journal of Alzheimer s Disease ◽

10.4061/2011/431320 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Takayuki Suzuki ◽

Kazuma Murakami ◽

Naotaka Izuo ◽

Toshiaki Kume ◽

Akinori Akaike ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Conformational Change ◽

Deletion Mutant ◽

Protein A ◽

Type A ◽

Synaptic Dysfunction ◽

Wild Type ◽

Radical Production

Oligomers of 40- or 42-mer amyloidβ-protein (Aβ40, Aβ42) cause cognitive decline and synaptic dysfunction in Alzheimer's disease. We proposed the importance of a turn at Glu22 and Asp23 of Aβ42 to induce its neurotoxicity through the formation of radicals. Recently, a novel deletion mutant at Glu22 (E22Δ) of Aβ42 was reported to accelerate oligomerization and synaptotoxicity. To investigate this mechanism, the effects of the E22Δ mutation in Aβ42 and Aβ40 on the transformation ofβ-sheets, radical production, and neurotoxicity were examined. Both mutants promotedβ-sheet transformation and the formation of radicals, while their neurotoxicity was negative. In contrast, E22P-Aβ42 with a turn at Glu22 and Asp23 exhibited potent neurotoxicity along with the ability to form radicals and potent synaptotoxicity. These data suggest that conformational change in E22Δ-Aβis similar to that in E22P-Aβ42 but not the same, since E22Δ-Aβ42 exhibited no cytotoxicity, unlike E22P-Aβ42 and wild-type Aβ42.

Download Full-text

Gene knockout of 5-lipoxygenase rescues synaptic dysfunction and improves memory in the triple-transgenic model of Alzheimer's disease

Molecular Psychiatry ◽

10.1038/mp.2013.23 ◽

2013 ◽

Vol 19 (4) ◽

pp. 511-518 ◽

Cited By ~ 42

Author(s):

P F Giannopoulos ◽

J Chu ◽

Y B Joshi ◽

M Sperow ◽

J-G Li ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gene Knockout ◽

Synaptic Dysfunction ◽

Transgenic Model ◽

Model Of Alzheimer’S Disease

Download Full-text

Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-β-Induced Synaptic Dysfunction and Loss

Journal of Neuroscience ◽

10.1523/jneurosci.1873-18.2018 ◽

2018 ◽

Vol 39 (4) ◽

pp. 758-772 ◽

Cited By ~ 20

Author(s):

Santiago V. Salazar ◽

Timothy O. Cox ◽

Suho Lee ◽

A. Harrison Brody ◽

Annabel S. Chyung ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Disease Risk ◽

Amyloid Β ◽

Synaptic Dysfunction ◽

Disease Risk Factor

Download Full-text

Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽

10.3390/cells10113261 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3261

Author(s):

Xiao Liu ◽

Qian Zhou ◽

Jia-He Zhang ◽

Xiaoying Wang ◽

Xiumei Gao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Disease Model ◽

Amyloid Β ◽

Brain Lesions ◽

Synaptic Dysfunction ◽

Synaptic Loss ◽

And Function ◽

The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

Download Full-text

Phospholipase D2 Ablation Ameliorates Alzheimer's Disease-Linked Synaptic Dysfunction and Cognitive Deficits

Journal of Neuroscience ◽

10.1523/jneurosci.3317-10.2010 ◽

2010 ◽

Vol 30 (49) ◽

pp. 16419-16428 ◽

Cited By ~ 125

Author(s):

T. G. Oliveira ◽

R. B. Chan ◽

H. Tian ◽

M. Laredo ◽

G. Shui ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Deficits ◽

Synaptic Dysfunction ◽

Phospholipase D2

Download Full-text

Preclinical Alzheimer's disease

Reviews in Clinical Gerontology ◽

10.1017/s095925981400001x ◽

2014 ◽

Vol 24 (2) ◽

pp. 117-121

Author(s):

P Gil-Gregorio ◽

R Yubero-Pancorbo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Diagnostic Criteria ◽

Stage I ◽

Disease Stage ◽

Synaptic Dysfunction ◽

Preclinical Alzheimer’S Disease ◽

Cerebral Amyloidosis ◽

Three Stages

SummaryRecently, diagnostic criteria for preclinical Alzheimer's disease have been proposed. These describe and define three stages of disease. Stage I is focused on asymptomatic cerebral amyloidosis. Stage II includes evidence of synaptic dysfunction and/or early degeneration. Finally, stage III of the disease is characterized by the beginning of cognitive decline.

Download Full-text