Vaccine Development to Treat Alzheimer’s Disease Neuropathology in APP/PS1 Transgenic Mice

A novel vaccine addressing the major hallmarks of Alzheimer’s disease (AD), senile plaque-like deposits of amyloid beta-protein (Aβ), neurofibrillary tangle-like structures, and glial proinflammatory cytokines, has been developed. The present vaccine takes a new approach to circumvent failures of previous ones tested in mice and humans, including the Elan-Wyeth vaccine (AN1792), which caused massive T-cell activation, resulting in a meningoencephalitis-like reaction. The EB101 vaccine consists ofAβ1-42delivered in a novel immunogen-adjuvant composed of liposomes-containing sphingosine-1-phosphate (S1P). EB101 was administered to APPswe/PS1dE9 transgenic mice before and after AD-like pathological symptoms were detectable. Treatment with EB101 results in a marked reduction of Aβplaque burden, decrease of neurofibrillary tangle-like structure density, and attenuation of astrocytosis. In this transgenic mouse model, EB101 reduces the basal immunological interaction between the T cells and immune activation markers in the affected hippocampal/cortical areas, consistent with decreased amyloidosis-induced inflammation. Therefore, immunization with EB101 prevents and reverses AD-like neuropathology in a significant manner by halting disease progression without developing behavioral spatial deficits in transgenic mice.

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O1-06-05: Monoclonal antibodies selective for Aβ protofibrils reduce plaque burden in transgenic mice models of Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2006.05.065 ◽

2006 ◽

Vol 2 ◽

pp. S21-S21

Author(s):

Lars Lannfelt ◽

Dag Sehlin ◽

Hillevi Englund ◽

Anna Lord ◽

Ann-Sofi Johansson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Monoclonal Antibodies ◽

Transgenic Mice ◽

Plaque Burden

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Investigating Markers of the NLRP3 Inflammasome Pathway in Alzheimer’s Disease: A Human Post-Mortem Study

Genes ◽

10.3390/genes12111753 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1753

Author(s):

Hao Tang ◽

Michael Harte

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Expression ◽

Glial Cell ◽

Nlrp3 Inflammasome ◽

Cell Activation ◽

Temporal Cortex ◽

Activation Markers

Neuroinflammatory mechanisms with glial cell activation have been implicated in the pathogenic process of Alzheimer’s disease (AD). Activation of the NLRP3 inflammasome is an essential component of the neuroinflammatory response. A role for NLRP3 activation in AD is supported by both in vitro and in vivo preclinical studies with little direct investigation of AD brain tissue. RNA expression of genes of three glial cell markers, HLA-DRA, AIF-1 and GFAP; the components of the NLRP3 inflammasome NLRP3, ASC, and caspase-1; and downstream pre-inflammatory cytokines IL-1 β and IL-18, were investigated in the temporal cortex of AD patients and age- and sex-matched controls. Protein expression of GFAP was also assessed. Increases in both mRNA and protein expression were observed for GFAP in AD. There were no significant changes in other NLRP3 activation markers between groups. Our results indicate the involvement of astrocyte activation in AD, particularly in more severe patients. We found no evidence for the specific involvement of the NLRP3 inflammasome.

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The Alzheimer’s Disease–Associated Protein BACE1 Modulates T Cell Activation and Th17 Function

The Journal of Immunology ◽

10.4049/jimmunol.1800363 ◽

2019 ◽

Vol 203 (3) ◽

pp. 665-675 ◽

Cited By ~ 1

Author(s):

Gerard Hernandez-Mir ◽

Itay Raphael ◽

Shankar Revu ◽

Catherine H. Poholek ◽

Lyndsay Avery ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

T Cell ◽

T Cell Activation ◽

Cell Activation

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EDITORIAL: BLOOD TESTS FOR ALZHEIMER’S DISEASE AND RELATED DISORDERS

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2019.20 ◽

2019 ◽

pp. 1-2

Author(s):

E.M. Reiman

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Task Force ◽

Neurofibrillary Tangle ◽

Neuritic Plaque ◽

Plaque Burden ◽

Neurofilament Light ◽

Task Force Report ◽

Blood Tests ◽

Wide Range

This issue of the Journal of Prevention of Alzheimer’s Disease (AD) includes a timely Clinical Trials on AD Task Force Report on promising blood tests for AD and related disorders (1). It highlights the promise of recently developed plasma amyloid-β42/40 (Aβ42/40) measurements for the assessment of neuritic plaque burden (e.g., reference 2), ultrasensitive neurofilament light (NfL) measurements for the assessment of ongoing neuroaxonal injury in a wide range of neurological disorders (3), and their potential roles in evaluation of interventions to treat and prevent the clinical onset of AD. It also considers recently developed plasma total-tau measurements, an indicator of neuronal injury and/or Aβ-mediated tau secretion (4), plasma phospho-tau measurements, a potential indicator of neurofibrillary tangle burden, and the ongoing effort to develop high-dimensional plasma genomic, transcriptomic, metabolomic, lipidomic, and proteomic profiles.

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Yeast-Based Aβ1-15 Vaccine Elicits Strong Immunogenicity and Attenuates Neuropathology and Cognitive Deficits in Alzheimer’s Disease Transgenic Mice

Vaccines ◽

10.3390/vaccines8030351 ◽

2020 ◽

Vol 8 (3) ◽

pp. 351

Author(s):

Dong-qun Liu ◽

Shuai Lu ◽

Lun Zhang ◽

Ya-ru Huang ◽

Mei Ji ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Wall ◽

Transgenic Mice ◽

Cognitive Deficits ◽

Plaque Burden ◽

High Antibody ◽

Safety And Efficacy ◽

Antibody Titers ◽

Promising Treatment

Immunotherapy focusing on reducing the amyloid-beta (Aβ) burden is a promising treatment strategy for Alzheimer’s disease (AD). Many clinical studies on AD immunotherapies have failed due to low safety and efficacy, calling for a highly potent AD vaccine which induces sufficient antibody titer while avoiding side effects. Here, we designed a yeast-based vaccine Y-5A15 comprising five copies of Aβ1-15 displayed on the surface of yeast cell wall, and we subcutaneously immunized APP/PS1 mice three times. Our results demonstrated that the Y-5A15 remarkably enhanced the Aβ epitope immunogenicity and elicited high antibody titers against Aβ in AD mice. Importantly, Y-5A15 vaccination successfully reduced Aβ levels, plaque burden and glial activation, rescued synaptic deficits and significantly ameliorated memory and cognitive decline in APP/PS1 transgenic mice, suggesting that the yeast-based Aβ epitope vaccine has a promising potency for the treatment of AD.

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Correlation between senile plaque and neurofibrillary tangle counts in cerebral cortex and neuronal counts in cortex and subcortical structures in Alzheimer's disease

Neuroscience Letters ◽

10.1016/0304-3940(85)90439-2 ◽

1985 ◽

Vol 56 (1) ◽

pp. 51-55 ◽

Cited By ~ 90

Author(s):

David M.A. Mann ◽

Peter O. Yates ◽

Borys Marcyniuk

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Cortex ◽

Senile Plaque ◽

Neurofibrillary Tangle ◽

Subcortical Structures

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microRNA-132/212 deficiency enhances Aβ production and senile plaque deposition in Alzheimer’s disease triple transgenic mice

Scientific Reports ◽

10.1038/srep30953 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 35

Author(s):

Julia Hernandez-Rapp ◽

Sara Rainone ◽

Claudia Goupil ◽

Véronique Dorval ◽

Pascal Y. Smith ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Senile Plaque ◽

Plaque Deposition ◽

Aβ Production

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Water influx into cerebrospinal fluid is significantly reduced in senile plaque bearing transgenic mice, supporting beta-amyloid clearance hypothesis of Alzheimer’s disease

Neurological Research ◽

10.1179/1743132814y.0000000434 ◽

2014 ◽

Vol 36 (12) ◽

pp. 1094-1098 ◽

Cited By ~ 24

Author(s):

Hironaka Igarashi ◽

Yuji Suzuki ◽

Ingrid L. Kwee ◽

Tsutomu Nakada

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Transgenic Mice ◽

Senile Plaque ◽

Beta Amyloid ◽

Water Influx

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Applying fluid biomarkers to Alzheimer's disease

AJP Cell Physiology ◽

10.1152/ajpcell.00007.2017 ◽

2017 ◽

Vol 313 (1) ◽

pp. C3-C10 ◽

Cited By ~ 29

Author(s):

Henrik Zetterberg

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Medial Temporal Lobe ◽

Clinical Symptoms ◽

Senile Plaque ◽

Neurofibrillary Tangle ◽

Amyloid Β ◽

Differential Diagnoses ◽

Blood Tests ◽

The Brain

Alzheimer’s disease (AD) is a common neurodegenerative disease that starts with a clinically silent phase of a decade or more during which brain pathologies accumulate predominantly in the medial temporal lobe but also elsewhere in the brain. Network dysfunction and clinical symptoms typically appear when senile plaque (amyloid-β) and neurofibrillary tangle (tau) pathologies meet in the brain parenchyma, producing synapse and neuronal loss. For plaque and tangle pathologies, reliable fluid biomarkers have been developed. These require sampling of cerebrospinal fluid. Reliable blood tests for plaque and tangle pathologies are currently lacking, but blood tests for general neurodegeneration have recently been developed. In AD, plaques and tangles often coexist with other pathologies, including Lewy bodies, and to what extent these contribute to symptoms is currently unknown. There are also important differential diagnoses that may be possible to distinguish from AD with the aid of biomarkers. The scope of this review is fluid biomarkers for AD and related pathologies. The purpose is to provide the reader with an updated account of currently available fluid biomarkers for AD and clinically relevant differential diagnoses.

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