Advances with RNA interference in Alzheimer’s disease research

Figures & data

Figure 1 A normal neuron (left) and an Alzheimer’s disease-affected neuron (right).

Note: Extracellular amyloid plaques and intracellular neurofibrillary tangles are the main pathological characteristics of the latter. Copyright © 1988. Proceedings of the National Academy of Sciences of the United States of America. Adapted with permission from Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A. 1988;85(11):4051–4055.⁵ Copyright © 1989. Elsevier. Adapted with permission from Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron. 1989;3(4):519–526.⁶

Figure 2 Hypothetical pathogenetic steps of the amyloid cascade hypothesis.

Note: Copyright © 2002, The American Association for the Advancement of Science. Reproduced with permission from Hardy JA, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–356.⁷

Figure 3 The mechanism of RNA interference.

Notes: Long double-stranded RNA (dsRNA) is introduced into the cytoplasm, where it is cleaved into small interfering RNA (siRNA) by the enzyme Dicer. Alternatively, siRNA can be introduced directly into the cell. The siRNA is then incorporated into the RNA-induced silencing complex (RiSC), resulting in the cleavage of the sense strand of RNA by argonaute2 (Ago2). The activated RiSC-siRNA complex seeks out, binds to and degrades complementary mRNA, which leads to the silencing of the target gene. The activated RiSC-siRNA complex can then be recycled for the destruction of identical mRNA targets. Copyright © 2009. Nature Publishing Group. Reproduced with permission from Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2009;8(2):129–138.⁹²

Table 1 Comparison of RNAi with traditional pharmaceutical drugs

Small molecules	Biologics (proteins and antibodies)	RNAi
Antagonist or agonist of targets	Antagonist or agonist of targets	Antagonist only
Extracellular and intracellular targets	Extracellular targets	All targets, including non-druggable targets
Not all targets can be modulated selectively and potently	High selectivity and potency	High selectivity and potency
No allelic specificity	Low allelic specificity	High allelic specificity
Lead ID and optimization slow	Lead ID and optimization slow	Lead ID and optimization rapid
Low cross species reactivity	Low cross species reactivity	High cross species reactivity
Easy to manufacture	Difficult to manufacture	Easy to synthesize and manufacture
Easy to deliver	Difficult to deliver	Difficult to deliver

Notes: The principal advantages of RNAi over small-molecule and protein therapeutics are that all targets, including “druggable” and “non-druggable” targets, extracellular and intracellular targets, and mutant alleles can be targeted with RNAi. One of the major advantages of sequence-based targeting technologies is the ability to design precisely targeted therapeutics for almost any target sequence, both coding and non-coding, regardless of the function of the gene product, whether that function is known, and in the absence of any target protein structure information. Copyright © 2006. Nature Publishing Group. Reproduced with permission from Bumcrot D, Manoharan M, Koteliansky v, Sah DW. RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol. 2006;2(12):711–719.⁹⁶

Abbreviations: RNAi, RNA interference; ID, identification.

Figure 4 Proteolytic processing of APP by á-, ß-, and ã-secretase.

Notes: Sequential APP cleavage by ß- and ã-secretase is referred to as the “amyloidogenic pathway” and generates Aß. Beta-secretase cleavage occurs within the ectodomain of APP close to the transmembrane domain, resulting in the shedding of the membrane-bound C-terminal fragment C99 (C-terminal 99 amino acid of APP). Gamma-secretase cleavage of C99 leads to Aß secretion and the formation of the APP intracellular domain (AICD). In the alternative, non-amyloidogenic pathway, APP is first cleaved by the metalloprotease a-secretase. This cleavage yields the soluble APP ectodomain sAPP á and a C-teminal fragment (C83), which is further processed by ã-secretase, leading to the secreted p3-peptide and AiCD. Copyright © 2006, BioMed Central. Reproduced with permission from Zheng H, Koo EH. The amyloid precursor protein: beyond amyloid. Mol Neurodegener. 2006;1:5.²⁰
Abbreviation: APP, amyloid precursor protein.

Figure 5 (A) Tau facilitates microtubule stabilization within cells and is particularly abundant in neurons. (B) it is thought that tau function is compromised in Alzheimer’s disease and other tauopathies.

Notes: This probably results from both tau hyperphosphorylation, which reduces the binding of tau to microtubules, and the sequestration of hyperphosphorylated tau into neurofibrillary tangles (NFTs), which reduces the amount of tau that is available to bind microtubules. The loss of tau function leads to microtubule instability and reduced axonal transport, which could contribute to neuropathology. Copyright © 2009. Nature Publishing Group. Reproduced with permission from Brunden KR, Trojanowski JQ, Lee VM. Advances in tau-focused drug discovery for Alzheimer’s disease and related tauopathies. Nat Rev Drug Discov. 2009;8(10):783–793.⁹⁷

Goedert M Wischik CM Crowther RA Walker JE Klug A Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau Proc Natl Acad Sci U S A 1988 85 11 4051 4055 3131773

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Goedert M Spillantini MG Jakes R Rutherford D Crowther RA Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease Neuron 1989 3 4 519 526 2484340

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Hardy JA Selkoe DJ The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics Science 2002 297 5580 353 356 12130773

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Whitehead KA Langer R Anderson DG Knocking down barriers: advances in siRNA delivery Nat Rev Drug Discov 2009 8 2 129 138 19180106

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Bumcrot D Manoharan M Koteliansky V Sah DW RNAi therapeutics: a potential new class of pharmaceutical drugs Nat Chem Biol 2006 2 12 711 719 17108989

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Zheng H Koo EH The amyloid precursor protein: beyond amyloid Mol Neurodegener 2006 1 5 16930452

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Brunden KR Trojanowski JQ Lee VM Advances in tau-focused drug discovery for Alzheimer’s disease and related tauopathies Nat Rev Drug Discov 2009 8 10 783 793 19794442

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