Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes

The strongest genetic risk factor influencing susceptibility to late-onset Alzheimer’s disease (AD) is apolipoprotein E (APOE) genotype. APOE has three common isoforms in humans, E2, E3, and E4. The presence of two copies of the E4 allele increases risk by ∼12-fold whereas E2 allele is associated with an ∼twofold decreased risk for AD. These data put APOE central to AD pathophysiology, but it is not yet clear how APOE alleles modify AD risk. Recently we found that astrocytes, a major central nervous system cell type that produces APOE, are highly phagocytic and participate in normal synapse pruning and turnover. Here, we report a novel role for APOE in controlling the phagocytic capacity of astrocytes that is highly dependent on APOE isoform. APOE2 enhances the rate of phagocytosis of synapses by astrocytes, whereas APO4 decreases it. We also found that the amount of C1q protein accumulation in hippocampus, which may represent the accumulation of senescent synapses with enhanced vulnerability to complement-mediated degeneration, is highly dependent on APOE alleles: C1q accumulation was significantly reduced in APOE2 knock-in (KI) animals and was significantly increased in APOE4 KI animals compared with APOE3 KI animals. These studies reveal a novel allele-dependent role for APOE in regulating the rate of synapse pruning by astrocytes. They also suggest the hypothesis that AD susceptibility of APOE4 may originate in part from defective phagocytic capacity of astrocytes which accelerates the rate of accumulation of C1q-coated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.

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Interaction of Alzheimer’s Disease-Associated Genetic Risk with Indicators of Socioeconomic Position on Mild Cognitive Impairment in the Heinz Nixdorf Recall Study

Journal of Alzheimer s Disease ◽

10.3233/jad-210244 ◽

2021 ◽

pp. 1-11

Author(s):

Mirjam Frank ◽

Jonas Hensel ◽

Lisa Baak ◽

Sara Schramm ◽

Nico Dragano ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Socioeconomic Position ◽

Genetic Risk ◽

Late Onset ◽

Heinz Nixdorf Recall Study ◽

Low Education ◽

Additive Scale

Background: The apolipoprotein E (APOE) ɛ4 allele is reported to be a strong genetic risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Additional genetic loci have been detected that influence the risk for late-onset AD. As socioeconomic position (SEP) is also strongly related to cognitive decline, SEP has been suggested to be a possible modifier of the genetic effect on MCI. Objective: To investigate whether APOE ɛ4 and a genetic sum score of AD-associated risk alleles (GRSAD) interact with SEP indicators to affect MCI in a population-based cohort. Methods: Using data of 3,834 participants of the Heinz Nixdorf Recall Study, APOE ɛ4 and GRSAD by SEP interactions were assessed using logistic regression models, as well as SEP-stratified genetic association analysis. Interaction on additive scale was calculated using the relative excess risk due to interaction (RERI). All analysis were additionally stratified by sex. Results: Indication for interaction on the additive scale was found between APOE ɛ4 and low education on MCI (RERI: 0.52 [95% -confidence interval (CI): 0.01; 1.03]). The strongest genetic effects of the APOE ɛ4 genotype on MCI were observed in groups of low education (Odds ratio (OR): 1.46 [95% -CI: 0.79; 2.63] for≤10 years of education versus OR: 1.00 [95% -CI: 0.43; 2.14] for≥18 years of education). Sex stratified results showed stronger effects in women. No indication for interaction between the GRSAD and SEP indicators on MCI was observed. Conclusion: Results indicate that low education may have an impact on APOE ɛ4 expression on MCI, especially among women.

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Aerobic exercise improves hippocampal blood flow for hypertensive Apolipoprotein E4 carriers

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x21990342 ◽

2021 ◽

pp. 0271678X2199034

Author(s):

Carolyn S Kaufman ◽

Robyn A Honea ◽

Joseph Pleen ◽

Rebecca J Lepping ◽

Amber Watts ◽

...

Keyword(s):

Blood Flow ◽

Aerobic Exercise ◽

Genetic Risk ◽

Exercise Intervention ◽

Late Onset ◽

Control Group ◽

Carrier Status ◽

Or Education ◽

Exercise Interventions ◽

Apolipoprotein E4

Cerebrovascular dysfunction likely contributes causally to Alzheimer’s disease (AD). The strongest genetic risk factor for late-onset AD, Apolipoprotein E4 ( APOE4), may act synergistically with vascular risk to cause dementia. Therefore, interventions that improve vascular health, such as exercise, may be particularly beneficial for APOE4 carriers. We assigned cognitively normal adults (65–87 years) to an aerobic exercise intervention or education only. Arterial spin labeling MRI measured hippocampal blood flow (HBF) before and after the 52-week intervention. We selected participants with hypertension at enrollment (n = 44). For APOE4 carriers, change in HBF (ΔHBF) was significantly ( p = 0.006) higher for participants in the exercise intervention (4.09 mL/100g/min) than the control group (−2.08 mL/100g/min). There was no difference in ΔHBF between the control (−0.32 mL/100g/min) and exercise (−0.54 mL/100g/min) groups for non-carriers (p = 0.918). Additionally, a multiple regression showed an interaction between change in systolic blood pressure (ΔSBP) and APOE4 carrier status on ΔHBF ( p = 0.035), with reductions in SBP increasing HBF for APOE4 carriers only. Aerobic exercise improved HBF for hypertensive APOE4 carriers only. Additionally, only APOE4 carriers exhibited an inverse relationship between ΔSBP and ΔHBF. This suggests exercise interventions, particularly those that lower SBP, may be beneficial for individuals at highest genetic risk of AD. ClinicalTrials.gov Identifier: NCT02000583

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Metallothionein prevents neurodegeneration and central nervous system cell death after treatment with gliotoxin 6-aminonicotinamide

Journal of Neuroscience Research ◽

10.1002/jnr.20154 ◽

2004 ◽

Vol 77 (1) ◽

pp. 35-53 ◽

Cited By ~ 18

Author(s):

Milena Penkowa ◽

Albert Quintana ◽

Javier Carrasco ◽

Mercedes Giralt ◽

Amalia Molinero ◽

...

Keyword(s):

Central Nervous System ◽

Cell Death ◽

Nervous System ◽

Central Nervous System Cell ◽

System Cell

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ApoE4 attenuates cortical neuronal activity and impairs memory in young apoE4 rats

10.1101/2021.01.14.426651 ◽

2021 ◽

Author(s):

Ilona Har-Paz ◽

Elor Arieli ◽

Anan Moran

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Neuronal Activity ◽

Genetic Risk ◽

Cortical Neurons ◽

Late Onset ◽

Genetic Risk Factor ◽

Normal Brain ◽

Brain Functions

AbstractThe E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD related neuropathology. Understanding these primary dysfunctions is vital for early detection of AD and the development of therapeutic strategies for it. Recently we have shown impaired extra-hippocampal memory in young apoE4 mice – a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we test the hypothesis that these early structural deficits impact learning via changes in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 and wildtype rats, before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young apoE4 rats showed impaired CTA learning, consistent with our previous results in apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Single neuron and ensemble analyses of taste coding demonstrated that apoE4 neurons could be used to correctly classify tastes, but were unable to undergo plasticity to support learning. Our results suggest that apoE4 impacts brain excitability and plasticity early in life and may act as an initiator for later AD pathologies.Significant statementThe ApoE4 allele is the strongest genetic risk-factor for late-onset Alzheimer’s disease (AD), yet the link between apoE4 and AD is still unclear. Recent molecular and in-vitro studies suggest that apoE4 interferes with normal brain functions decades before the development of its related AD neuropathology. Here we recorded the activity of cortical neurons from young apoE4 rats during extra-hippocampal learning to study early apoE4 neuronal activity abnormalities, and their effects over coding capacities. We show that apoE4 drastically reduces basal and stimuli-evoked cortical activity in both excitatory and inhibitory neurons. The apoE4-induced activity attenuation did not prevent coding of stimuli identity and valence, but impaired capacity to undergo activity changes to support learning. Our findings support the hypothesis that apoE4 interfere with normal neuronal plasticity early in life; a deficit that may lead to late-onset AD development.

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ApoE4 attenuates autophagy via FoxO3a repression in the brain

Scientific Reports ◽

10.1038/s41598-021-97117-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hee-Young Sohn ◽

Seong-Ik Kim ◽

Jee-Yun Park ◽

Sung-Hye Park ◽

Young Ho Koh ◽

...

Keyword(s):

Genetic Risk ◽

Late Onset ◽

Multiple Roles ◽

Lipid Transport ◽

Phosphorylated Tau ◽

Phosphorylation Level ◽

Ε4 Allele ◽

Human Brains ◽

The Brain ◽

Novel Therapeutic

AbstractApolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 allele of APOE is the highest genetic risk factor for developing late-onset Alzheimer’s disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.

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Central Nervous System Cell-Derived Exosomes in Neurodegenerative Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9965564 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Yang Tian ◽

Chen Fu ◽

Yifan Wu ◽

Yao Lu ◽

Xuemei Liu ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neurodegenerative Diseases ◽

Extracellular Vesicles ◽

Mammalian Cells ◽

Glia Cells ◽

Central Nervous System Cell ◽

The Central Nervous System ◽

System Cell ◽

Almost All

Exosomes are a type of extracellular vesicles secreted by almost all kinds of mammalian cells that shuttle “cargo” from one cell to another, indicative of its role in cell-to-cell transportation. Interestingly, exosomes are known to undergo alterations or serve as a pathway in multiple diseases, including neurodegenerative diseases. In the central nervous system (CNS), exosomes originating from neurons or glia cells contribute to or inhibit the progression of CNS-related diseases in special ways. In lieu of this, the current study investigated the effect of CNS cell-derived exosomes on different neurodegenerative diseases.

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CHAPTER 19. Smart Materials for Central Nervous System Cell Delivery and Tissue Engineering

Smart Materials for Tissue Engineering - Smart Materials Series ◽

10.1039/9781788010542-00529 ◽

2017 ◽

pp. 529-557 ◽

Cited By ~ 5

Author(s):

Timothy M. O’Shea ◽

Alexander L. Wollenberg ◽

Alexander M. Bernstein ◽

Darren B. Sarte ◽

Timothy J. Deming ◽

...

Keyword(s):

Tissue Engineering ◽

Central Nervous System ◽

Nervous System ◽

Smart Materials ◽

Cell Delivery ◽

Central Nervous System Cell ◽

System Cell

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Protein complexity of central nervous system cell lines

Journal of Neuroscience ◽

10.1523/jneurosci.06-10-02829.1986 ◽

1986 ◽

Vol 6 (10) ◽

pp. 2829-2836 ◽

Cited By ~ 13

Author(s):

D Schubert ◽

B Brass ◽

JP Dumas

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Cell Lines ◽

Central Nervous System Cell ◽

System Cell

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Late-onset schizophrenia

Oxford Textbook of Old Age Psychiatry ◽

10.1093/med/9780198807292.003.0043 ◽

2020 ◽

pp. 671-694

Author(s):

Ellen E. Lee ◽

Baichun Hou ◽

Ipsit V. Vahia ◽

Dilip V. Jeste

Keyword(s):

Risk Factors ◽

Differential Diagnosis ◽

Life Events ◽

Genetic Risk ◽

Psychiatric Symptoms ◽

Late Onset ◽

Sociodemographic Factors ◽

Sensory Loss ◽

Adverse Life Events

Late-onset schizophrenia remains an understudied subtype of schizophrenia, despite growing recognition of its impact and distinction from early-onset schizophrenia. This chapter reviews the existing literature on late-onset schizophrenia including beginning with the nomenclature and epidemiology. Then we provide a review of key risk factors and correlates—including genetic risk, sex differences, comorbid sensory loss and physical illness, cognitive and psychiatric symptoms, sociodemographic factors, adverse life events, neuropathology, and inflammation. The chapter ends with clinical issues, including symptoms, differential diagnosis, treatments, and prognosis. Recent studies have examined the role of oestrogen treatments and a new therapy for tardive dyskinesia therapy as well as inflammatory mechanisms in schizophrenia.

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