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Genomics of Alzheimer Disease A Review

Roger N. Rosenberg, MD1,2; Doris Lambracht-Washington, PhD1; Gang Yu, PhD3; Weiming Xia, PhD4,5
[+] Author Affiliations
1Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas
2Editor, JAMA Neurology
3Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas
4Geriatric Research, Education and Clinical Center, Bedford Veterans Hospital, Bedford, Massachusetts
5Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
JAMA Neurol. 2016;73(7):867-874. doi:10.1001/jamaneurol.2016.0301.
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Importance  To provide a comprehensive review of knowledge of the genomics of Alzheimer disease (AD) and DNA amyloid β 42 (Aβ42) vaccination as a potential therapy.

Observations  Genotype-phenotype correlations of AD are presented to provide a comprehensive appreciation of the spectrum of disease causation. Alzheimer disease is caused in part by the overproduction and lack of clearance of Aβ protein. Oligomer Aβ, the most toxic species of Aβ, causes direct injury to neurons, accompanied by enhanced neuroinflammation, astrocytosis and gliosis, and eventually neuronal loss. The strongest genetic evidence supporting this hypothesis derives from mutations in the amyloid precursor protein (APP) gene. A detrimental APP mutation at the β-secretase cleavage site linked to early-onset AD found in a Swedish pedigree enhances Aβ production, in contrast to a beneficial mutation 2 residues away in APP that reduces Aβ production and protects against the onset of sporadic AD. A number of common variants associated with late-onset AD have been identified including apolipoprotein E, BIN1, ABC7, PICALM, MS4A4E/MS4A6A, CD2Ap, CD33, EPHA1, CLU, CR1, and SORL1. One or 2 copies of the apolipoprotein E ε4 allele are a major risk factor for late-onset AD. With DNA Aβ42 vaccination, a Th2-type noninflammatory immune response was achieved with a downregulation of Aβ42-specific effector (Th1, Th17, and Th2) cell responses at later immunization times. DNA Aβ42 vaccination upregulated T regulator cells (CD4+, CD25+, and FoxP3+) and its cytokine interleukin 10, resulting in downregulation of T effectors.

Conclusions and Relevance  Mutations in APP and PS-1 and PS-2 genes that are associated with early-onset, autosomal, dominantly inherited AD, in addition to the at-risk gene polymorphisms responsible for late-onset AD, all indicate a direct and early role of Aβ in the pathogenesis of AD. A translational result of genomic research has been Aβ-reducing therapies including DNA Aβ42 vaccination as a promising approach to delay or prevent this disease.

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Figure 1.
Proteolytic Processing of Amyloid Precursor Protein (APP) by β- and γ-Secretases to Generate Amyloid β (Aβ) Protein

When APP undergoes nonamyloidogenic proteolytic cleavage by α- and γ-secretases, p3 instead of Aβ is generated. A small number of APP molecules is proteolytically processed by β-secretase and generates an N-terminal soluble APP and a 12-kDa C-terminal stub of APP, which is cleaved by γ-secretase to yield Aβ and amyloid intracellular domain. The PS1 and PS2 genes carry the active site of γ-secretase complex. Proteins encoded by multiple risk genes associated with late-onset Alzheimer disease are involved in Aβ clearance. The SORL1, PICALM, and CD2AP genes regulate APP endocytosis (vs retromer-mediated APP recycling) and Aβ generation in endosome-lysosomes.

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Figure 2.
Double DNA Plasmid System Incorporating GAL4/Upstream Activating Sequences to Increase Amyloid β 42 (Aβ42) Expression

It consists of 2 plasmids, an activator plasmid encoding the yeast GAL4 transcription factor and a responder plasmid encoding Aβ1-42 for which its expression is driven by binding of GAL4 to upstream activating sequences (UAS sites) in front of a minimal promoter. The open reading frame for Aβ42 was synthesized 3 times in a row, encoding DNA Aβ42 trimer. Aβ42-trimer/UAS responder plasmid and GAL4 activator plasmid are mixed in a ratio of 1 to 0.75 for preparation of the DNA-coated gold particles. The GAL4 protein binds as a homodimer to UAS sites present on the responder plasmid. GAL4 binding enhances transcription of the Aβ42 trimer sequence, which is cloned into a DNA fragment containing an adenovirus E3 leader sequence and an endosomal targeting sequence derived from the mouse MHC class II gene, H2-DM. The final protein product has a size of about 21 kD.20

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Figure 3.
Reductions of Amyloid β 42 (Aβ42) in DNA Aβ42 Trimer Immunized Amyloid Precursor Protein/Presenilin 1 (APP/PS1) Double Transgenic Mice and the Respective Control DNA Immunized Mice

Shown is the amount of Aβ42 peptide per gram of wet brain tissue (μg/g). Immunization was started in both groups in 3-month-old mice and was continued for 11 immunizations until the mice were 12 months old. Group A was killed for final analyses (plasma antibody levels, brain Aβ histology and biochemistry) 14 days following the last immunization, while mice in group B were killed 4 months following the 11th immunization. In both groups, a significant reduction of Aβ1-42 levels in the brain was found in comparison with the respective control groups (DNA Luc control DNA immunized mice). Group A showed an amyloid reduction of 65% to 53% while group B showed a reduction of Aβ1-42 brain levels of 25%. Reproduced with permission from ImmunoTargets and Therapy.110

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