Amyloid β peptide as a vaccine for Alzheimer's disease involves receptor-mediated transport at the blood–brain barrier

One of the key hallmarks of Alzheimer’s disease is the aggregation of the amyloid-β peptide to form fibrils. Consequently, there has been great interest in studying molecules that can disrupt...

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Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.695479 ◽

2021 ◽

Vol 15 ◽

Author(s):

Dong Wang ◽

Fanglian Chen ◽

Zhaoli Han ◽

Zhenyu Yin ◽

Xintong Ge ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Brain Barrier ◽

Amyloid Β ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Factors Affecting ◽

Blood Brain ◽

Normal Metabolism

Amyloid-β (Aβ) is the predominant pathologic protein in Alzheimer’s disease (AD). The production and deposition of Aβ are important factors affecting AD progression and prognosis. The deposition of neurotoxic Aβ contributes to damage of the blood–brain barrier. However, the BBB is also crucial in maintaining the normal metabolism of Aβ, and dysfunction of the BBB aggravates Aβ deposition. This review characterizes Aβ deposition and BBB damage in AD, summarizes their interactions, and details their respective mechanisms.

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Lipopolysaccharide alters the blood–brain barrier transport of amyloid β protein: A mechanism for inflammation in the progression of Alzheimer’s disease

Brain Behavior and Immunity ◽

10.1016/j.bbi.2009.01.017 ◽

2009 ◽

Vol 23 (4) ◽

pp. 507-517 ◽

Cited By ~ 139

Author(s):

Laura B. Jaeger ◽

Shinya Dohgu ◽

Rukhsana Sultana ◽

Jessica L. Lynch ◽

Joshua B. Owen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Brain Barrier ◽

Protein A ◽

Amyloid Β ◽

Brain Barrier ◽

Amyloid Β Protein ◽

Blood Brain ◽

Β Protein

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Alzheimer’s disease: A matter of blood–brain barrier dysfunction?

Journal of Experimental Medicine ◽

10.1084/jem.20171406 ◽

2017 ◽

Vol 214 (11) ◽

pp. 3151-3169 ◽

Cited By ~ 191

Author(s):

Axel Montagne ◽

Zhen Zhao ◽

Berislav V. Zlokovic

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Brain Barrier ◽

Amyloid Β ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Neurodegenerative Process ◽

Blood Brain ◽

Underlying Mechanisms

The blood–brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been shown in Alzheimer’s disease (AD) before dementia, neurodegeneration and/or brain atrophy occur. However, the role of BBB breakdown in neurodegenerative disorders is still not fully understood. Here, we examine BBB breakdown in animal models frequently used to study the pathophysiology of AD, including transgenic mice expressing human amyloid-β precursor protein, presenilin 1, and tau mutations, and apolipoprotein E, the strongest genetic risk factor for AD. We discuss the role of BBB breakdown and dysfunction in neurodegenerative process, pitfalls in BBB measurements, and how targeting the BBB can influence the course of neurological disorder. Finally, we comment on future approaches and models to better define, at the cellular and molecular level, the underlying mechanisms between BBB breakdown and neurodegeneration as a basis for developing new therapies for BBB repair to control neurodegeneration.

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Blood-brain barrier–penetrating siRNA nanomedicine for Alzheimer’s disease therapy

Science Advances ◽

10.1126/sciadv.abc7031 ◽

2020 ◽

Vol 6 (41) ◽

pp. eabc7031 ◽

Cited By ~ 1

Author(s):

Yutong Zhou ◽

Feiyan Zhu ◽

Yang Liu ◽

Meng Zheng ◽

Yibin Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Brain Barrier ◽

Glucose Transporter ◽

Amyloid Β ◽

Cognitive Capacity ◽

Brain Barrier ◽

Great Promise ◽

Glucose Transporter 1 ◽

Blood Brain

Toxic aggregated amyloid-β accumulation is a key pathogenic event in Alzheimer’s disease (AD), which derives from amyloid precursor protein (APP) through sequential cleavage by BACE1 (β-site APP cleavage enzyme 1) and γ-secretase. Small interfering RNAs (siRNAs) show great promise for AD therapy by specific silencing of BACE1. However, lack of effective siRNA brain delivery approaches limits this strategy. Here, we developed a glycosylated “triple-interaction” stabilized polymeric siRNA nanomedicine (Gal-NP@siRNA) to target BACE1 in APP/PS1 transgenic AD mouse model. Gal-NP@siRNA exhibits superior blood stability and can efficiently penetrate the blood-brain barrier (BBB) via glycemia-controlled glucose transporter-1 (Glut1)–mediated transport, thereby ensuring that siRNAs decrease BACE1 expression and modify relative pathways. Noticeably, Gal-NP@siBACE1 administration restored the deterioration of cognitive capacity in AD mice without notable side effects. This “Trojan horse” strategy supports the utility of RNA interference therapy in neurodegenerative diseases.

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Ultrasound-mediated blood-brain barrier disruption improves anti-pyroglutamate3 Aβ antibody efficacy and enhances phagocyte infiltration into brain in aged Alzheimer’s disease-like mice

10.1101/2021.01.15.426806 ◽

2021 ◽

Author(s):

Qiaoqiao Shi ◽

Tao Sun ◽

Yongzhi Zhang ◽

Chanikarn Power ◽

Camilla Hoesch ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Blood Brain Barrier ◽

Combination Treatment ◽

Amyloid Β ◽

Brain Barrier ◽

Plaque Burden ◽

Spatial Learning And Memory ◽

Blood Brain

AbstractPyroglutamate-3 amyloid-β (pGlu3 Aβ) is an N-terminally modified, toxic form of amyloid-β that is present in cerebral amyloid plaques and vascular deposits. Using the Fc-competent murine anti-pGlu3 Aβ monoclonal antibody (mAb), 07/2a, we present here a nonpharmacological approach using focused ultrasound (FUS) with intravenous (i.v.) injection of microbubbles (MB) to facilitate i.v. delivery of the 07/2a mAb across the blood brain barrier (BBB) in order to improve Aβ removal and restore memory in aged APP/PS1 mice, an Alzheimer’s disease (AD)-like model of amyloidogenesis.Compared to sham-treated controls, aged APP/PS1 mice treated with 07/2a immediately prior to FUS-mediated BBB disruption (mAb + FUS-BBBD combination treatment) showed significantly better spatial learning and memory in the Water T Maze. FUS-BBBD treatment alone improved contextual fear learning and memory in aged WT and APP/PS1 mice, respectively. APP/PS1 mice given the combination treatment had reduced Aβ42 and pGlu3 Aβ hippocampal plaque burden compared to PBS-treated APP/PS1 mice.Hippocampal synaptic puncta density and synaptosomal synaptic protein levels were also higher in APP/PS1 mice treated with 07/2a just prior to BBB disruption. Increased Iba-1+ microglia were observed in the hippocampi of AD mice treated with 07/2a with and without FUS-BBBD, and APP/PS1 mice that received hippocampal BBB disruption and 07/2a showed increased Ly6G+ monocytes in hippocampal CA3. FUS-induced BBB disruption did not increase the incidence of microhemorrhage in mice with or without 07/2a mAb treatment.Our findings suggest that FUS is useful tool that may enhance delivery of an anti-pGlu3 Aβ mAb for immunotherapy. FUS-mediated BBB disruption in combination with the 07/2a mAb also appears to facilitate monocyte infiltration in this AD model. Overall, these effects resulted in greater sparing of synapses and improved cognitive function without causing overt damage, suggesting the possibility of FUS as a noninvasive method to increase the therapeutic efficacy in AD patients.

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Passage of amyloid β protein antibody across the blood–brain barrier in a mouse model of Alzheimer’s disease

Peptides ◽

10.1016/s0196-9781(02)00261-9 ◽

2002 ◽

Vol 23 (12) ◽

pp. 2223-2226 ◽

Cited By ~ 124

Author(s):

William A. Banks ◽

Brie Terrell ◽

Susan A. Farr ◽

Sandra M. Robinson ◽

Naoko Nonaka ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Blood Brain Barrier ◽

Amyloid Β ◽

Brain Barrier ◽

Amyloid Β Protein ◽

Blood Brain ◽

Model Of Alzheimer’S Disease ◽

Β Protein

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Time to test antibacterial therapy in Alzheimer’s disease

Brain ◽

10.1093/brain/awz244 ◽

2019 ◽

Cited By ~ 9

Author(s):

Francesco Panza ◽

Madia Lozupone ◽

Vincenzo Solfrizzi ◽

Mark Watling ◽

Bruno P Imbimbo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Blood Brain Barrier ◽

Amyloid Β ◽

The Other ◽

Brain Barrier ◽

The Past ◽

Blood Brain ◽

The Brain

Abstract Alzheimer’s disease is associated with cerebral accumulation of amyloid-β peptide and hyperphosphorylated tau. In the past 28 years, huge efforts have been made in attempting to treat the disease by reducing brain accumulation of amyloid-β in patients with Alzheimer’s disease, with no success. While anti-amyloid-β therapies continue to be tested in prodromal patients with Alzheimer’s disease and in subjects at risk of developing Alzheimer’s disease, there is an urgent need to provide therapeutic support to patients with established Alzheimer’s disease for whom current symptomatic treatment (acetylcholinesterase inhibitors and N-methyl d-aspartate antagonist) provide limited help. The possibility of an infectious aetiology for Alzheimer’s disease has been repeatedly postulated over the past three decades. Infiltration of the brain by pathogens may act as a trigger or co-factor for Alzheimer’s disease, with Herpes simplex virus type 1, Chlamydia pneumoniae, and Porphyromonas gingivalis being most frequently implicated. These pathogens may directly cross a weakened blood–brain barrier, reach the CNS and cause neurological damage by eliciting neuroinflammation. Alternatively, pathogens may cross a weakened intestinal barrier, reach vascular circulation and then cross blood–brain barrier or cause low grade chronic inflammation and subsequent neuroinflammation from the periphery. The gut microbiota comprises a complex community of microorganisms. Increased permeability of the gut and blood–brain barrier induced by microbiota dysbiosis may impact Alzheimer’s disease pathogenesis. Inflammatory microorganisms in gut microbiota are associated with peripheral inflammation and brain amyloid-β deposition in subjects with cognitive impairment. Oral microbiota may also influence Alzheimer’s disease risk through circulatory or neural access to the brain. At least two possibilities can be envisaged to explain the association of suspected pathogens and Alzheimer’s disease. One is that patients with Alzheimer’s disease are particularly prone to microbial infections. The other is that microbial infection is a contributing cause of Alzheimer’s disease. Therapeutic trials with antivirals and/or antibacterials could resolve this dilemma. Indeed, antiviral agents are being tested in patients with Alzheimer’s disease in double-blind placebo-controlled studies. Although combined antibiotic therapy was found to be effective in animal models of Alzheimer’s disease, antibacterial drugs are not being widely investigated in patients with Alzheimer’s disease. This is because it is not clear which bacterial populations in the gut of patients with Alzheimer’s disease are overexpressed and if safe, selective antibacterials are available for them. On the other hand, a bacterial protease inhibitor targeting P. gingivalis toxins is now being tested in patients with Alzheimer’s disease. Clinical studies are needed to test if countering bacterial infection may be beneficial in patients with established Alzheimer’s disease.

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