Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer’s disease

Figures & data

Figure 1 Disruption of the processing balance of the amyloid precursor protein (APP) in Alzheimer’s disease. The APP can be processed through two alternative pathways. In the α-secretase (α-sec) pathway (or nonamyloidogenic pathway), APP is cleaved by α-sec, which releases the soluble sAPPα N-terminal fragment, creating a membrane-tethered, C-terminal fragment of 83 amino acids (C83). α-Secretase (α-sec) cleavage occurs within the amyloid-β (Aβ) domain (shown in dark red) and precludes Aβ formation. C83 is further processed by γ-secretase (γ-sec) to produce the 3 kDa, nonamyloidogenic peptide p3 and release the APP intracellular domain (AICD, shown in light green) in the cytosol. In the β-secretase pathway (or amyloidogenic pathway), cleavage by β-site APP-cleaving enzyme (BACE1) releases the soluble APP N-terminal fragment (sAPPβ), which can be further processed by an unknown protease to liberate a fragment (shown in lilac) that can activate DR6 receptors. BACE1 cleavage of APP also produces the membrane-tethered C-terminal fragment of 99 amino acids (C99), which is the direct precursor to Aβ. Further processing of C99 by γ-sec achieves the release of Aβ in the extracellular or intravesicular space and AICD in the cytosol. When Aβ production reaches a threshold, the peptide self-aggregates to form toxic oligomers that trigger degeneration of neuronal cells by a mechanism that involves free radical formation and shifts the balance of APP processing towards the amyloidogenic pathway.

Figure 2 Schematic diagram of β-site amyloid precursor protein-cleaving enzyme (BACE)-1. BACE1 is translated as a precursor protein, with a signal peptide (SP) and a prosequence (Pro). The mature protein consists of a large enzymatic domain (in blue, with the two motifs that constitute the active site in yellow boxes; DTG stands for aspartyl-threonyl-glycyl and DSG for aspartyl-seryl-glycyl), a transmembrane domain (TM), and a short cytoplasmic domain (CD) containing an endosomal sorting sequence (white box; DISLL stands for aspartyl-isoleucyl-seryl-leucyl-leucyl). The four-leaf designs represent the N-glycosylation sites.

Figure 3 Published chemical structure of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in preclinical and clinical trials. The precise structure of Pfizer compound PF-05297909 has not been disclosed, but it is presumably derived from the general formula given in Brodney’s United States Patent and Trademark Office application 20110224231, where R1 and R1′ are each independently hydrogen, alkyl, or alkenyl, R2 is alkyl, cycloalkyl, or alkenyl, B is alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and A is independently aryl, cycloalkyl, heterocycloalkyl, or heteroaryl.

Table 1 Data of BACE1 inhibitors in clinical trials

Company and compound name	In vitro and cellular data	Animal studies	Clinical trial stage and outcomes	Comments and references
AstraZeneca AZD3839	Ki=26 nM/BACE 1 Selectivity l4-fold/BACE2; > 1,000-fold/Cath D ↓ Aβ and sAPPβ secretion in guinea pig cortical neurons	In mice, ↓ Aβ in brain and blood In guinea pigs, ↓ Aβ in brain and CSF In nonhuman primates, ↓ CSF Ap40, Ap42, sAPPβ	Phase 1 (2013)	120
Comentis/Astel las CTS-21166	Ki = 1.1 nM/BACE 1 ↓ Aβ secretion in CHO-APP cells (IC50 =39 nM)	Tg2576 mice, 8 mg/kg (intraperitoneal injection) 50% ↓ brain Aβ, 70% ↓ plasma Aβ	Phase 1 completed (2008) in healthy volunteers Well tolerated (up to 225 mg) ↓ Aβ in plasma	Low brain exposure?^Citation98
EISAI E2609	Cell-based assay, IC50 =7 nM	In rats, 10 mg/kg, -80% ↓ CSF Aβ and -55% ↓ brain Aβ In guinea pigs, 3–10 mg/kg, 85% ↓ CSF Aβ, 74% ↓ brain Aβ In nonhuman primates, ↓ plasma Aβ1–40 and Aβ1–42 equally (ED50 = 1.3 nmol/L)	Phase 1 completed. Well tolerated in healthy volunteers (young subjects given 5–800 mg, elderly cohort given 50 mg) 800 mg: 92% ↓ plasma Aβ1–x, 6 days’ lasting effect 25 mg: 46% ↓ CSF Aβ1–x 200 mg: 80% ↓ CSF Aβ1–x	Headache as side effect? Recruiting MCI patients for trials^Citation116^–^Citation119
Eli Lilly LY2811376	IC50 =239 nM/BACE 1 Lack of selectivity/Cath D ↓ Aβ secretion in HEK-APP cells (IC50 =300 nM)	In PDAPP mice, 10–100 mg/kg, 47%–68% ↓ brain Aβ, 56%-78% ↓ C99, 33%-63% ↓ sAPPβ In beagle dogs, 85% ↓ plasma Aβ, 70% ↓ brain Aβ	Phase 1 (2010) in healthy volunteers interrupted ↓ CSF Aβ and sAPPβ ↓ CSF sAPPα	Retinal toxicity^Citation105
Eli Lilly LY2886721	IC50=20.3 nM/BACE 1 Selectivity vs Cath D, pepsin and renin ↓ Aβ in HEK293Swe (ED50 = 18.7 nM) and in primary neurons from PDAPP mice (ED50= 10.7 nM)	In PDAPP mice, ↓ brain Aβ, C99, sAPPβ 3–30 mg/kg dose ↓ brain Aβ by 20%-65%. 9-hour lasting effect In beagle dogs, 0.5 mg/kg dose, 50% ↓ CSF Aβ, 24-hour effect	Phase 1 (2013) in healthy volunteers interrupted Single-dose trial (10 or 35 mg), and multiple-dose study (5, 15, or 35 mg) daily for 2 weeks ↓ CSF AP40, AP42, and sAPPβ	Liver toxicity^Citation106
Merck MK-8931	IC50 =6–50 nM/BACE 1 100 × selective vs Cath D ↓ Aβ secretion in cells (IC50 < 100 nM)	In TgCRND8 (SwAPP × InAPP) mice, 10 mg/kg, 35% ↓ brain Aβ plaques, modest improvement in behavior test In monkeys, 20–60 mg/kg, 14 days 90% ↓ CSF Aβ; 90% ↓ brain Aβ	Phase 1 (2010–2012) in healthy volunteers Well tolerated (2.5–550 mg) 20-hour half-life Single dose (100 or 500 mg), >90% ↓ CSF Aβ40 and Aβ42; multiple dose (10 mg), 50% ↓ CSF Aβ; 40 mg, 80% CSF ↓ Aβ In patients with mild to moderate, daily dose (12–80 mg) for 7 days ↓ CSF Aβ40, Aβ42, and sAPPβ	Phase II/III in progress^Citation112^–^Citation115

Abbreviations: BACE I, β-site amyloid precursor protein-cleaving enzyme; Cath D, cathepsin D; Aβ, amyloid-β; sAPP, soluble N-terminal fragment of amyloid precursor protein; IC₅₀, 50% inhibitory concentration; ED₅₀, 50% effective dose; CSF, cerebrospinal fluid; Tg, transgenic.

Table 2 List of identified BACEI substrates

Substrate protein	Biological function	Role of BACE1 cleavage	Consequence of BACE1 knockout, or inhibition	Consequence of BACEI increased expression
Amyloid precursor protein (APP)	– Regulation of neurite outgrowth, synapse formation, and synaptic plasticity^Citation21 – Metal homeostasis^Citation23	– Aβ production^Citation66 – sAPPβ ectodomain shedding, leading to activation of DR6, to regulate axon pruning^Citation28 – Regulation of cortical plasticity in adult?	– Suppression of Aβ production^Citation62^–^Citation64,Citation142 – Reduced plaque formation and rescue of cognitive deficits in AD models^Citation128,Citation141	– Aβ amyloid accumulation and neuronal death^Citation35,Citation37,Citation83
Amyloid precursor-1ike proteins (APLPI and APLP2)	– Regulation of neurite outgrowth, synapse formation, and synaptic plasticity^Citation21 – Glucose metabolism and insulin homeostasis^Citation210	– Ectodomain shedding	– Unknown	– Unknown
Neuregulin I (Nrgl) type IIIβl	– Regulation of myelination, oligodendrocyte differentiation, neuronal migration – Regulation of neurotransmitter receptors and synaptic plasticity^Citation144,Citation213,Citation214 – Regulation of muscle-spindle formation and maintenance^Citation214	– Nrgl type III precursor cleavage to induce activation of ErbB receptors^Citation144,Citation152,Citation211 – Nrgl type IIIβl cleavage to regulate formation and maintenance of muscle spindles^Citation159	– Hypomyelination of peripheral and central nervous systems^Citation144,Citation146 – Schizophrenia-like phenotypes improved by anti psychotics^Citation146 – Synaptic deficits^Citation212 – Deficits in motor coordination^Citation159	– Unknown
Neuregulin 3 (Nrg3) Voltage gated sodium channel (VGSC) auxiliary β-subunits β 1–4	– Remyeli nation^Citation149 – Regulation of sodium-channel activity (neuronal membrane - excitability and propagation of action potentials)^Citation162	– Cleavage activation^Citation149 – Cleavage of VGSC β-subunits to repress cell-surface expression of Na channels and regulate sodium currents^Citation164^–^Citation166	– Defective remyelination^Citation149 – Seizures^Citation142,Citation165	– Unknown – Epileptic activity
Potassium voltage-gated channel ancillary subunits KCNEI and KCNE2	– Modulation of potassium-channel trafficking and activity (membrane excitability in brain and heart)^Citation215	– Cleavage of KCNE to control potassium-channel activity and cell-surface expression^Citation171	– Seizures (unrelated to aberrant sodium-channel activity)^Citation170	– Unknown
Beta-galactoside alpha2,6-sialyltransferase (ST6Gal 1)	– Negative regulator of galectin (involved in adhesion, migration, proliferation, and apoptosis)^Citation216	– Down regulates transferase activity^Citation178	– Altered control of immune response? – Loss of control of cell adhesion and proliferation	– Reduced cancer proliferation?
P-selectin glycoprotein ligand-1 (PSGLI or SELPLG)	– Cell adhesion^Citation217 – Response to injury (recruitment of white blood cells to inflamed tissue)^Citation217	– Cleavage of SELPLG^Citation185 – Limits cell adhesion?	– Altered control of inflammatory response? – Autoimmune disease?	– Temper immune and inflammation mechanisms?
Interleukin I receptor 2 (IL1-R2)	– Decoy receptor for IL 1 – Regulates immune and inflammatory responses	– IL-R2 secretion^Citation186 – Limit inflammatory response?	– Loss of control of inflammatory response	– Modulate immune and inflammation mechanisms?
Low-density lipoprotein receptor-related protein (LRP)	– Endocytosis and lipid homeostasis (ApoE receptor)^Citation218 – Clearance mechanisms^Citation218	– Ectodomain shedding, LRPI secretion^Citation182	– Decreased lipid metabolism and Aβ clearance?	– Alteration of lipid metabolism and Aβ clearance?
L1 and close homologue of L1 (CHL1)	– Neural cell adhesion^Citation219 – Neuronal repair and plasticity	– Ectodomain shedding to control receptor cell-surface expression and neuronal adhesion^Citation174,Citation175	– Defects in axon guidance^Citation188^–^Citation190	– Unknown
Seizure protein 6 homologue (SEZ6)	– Axonal guidance and formation of neuronal circuits^Citation221	– Ectodomain shedding^Citation175,Citation187	– Defects in axon guidance^Citation188^–^Citation190 – Seizures^Citation170 – Synaptic deficits^Citation158	– Unknown
Contactin-2 (CNTN2 or Tag-1)	– Axonal guidance, formation of neuronal circuits and regeneration of sensory neurons^Citation222	– Not validated yet	– Defects in axon guidance^Citation186,Citation190 – Seizures^Citation170 – Synaptic deficits^Citation158	– Unknown
Vascular endothelial growth factor receptor 1 (VEGFR1)	– Tyrosine-kinase decoy receptor involved in regulating angiogenesis^Citation223	– Ectodomain shedding – Regulation of retinal angiogenesis	– Aberrant retinal vascularization^Citation191 – Loss of vision	– Unknown

Abbreviations: BACE1, β-site amyloid precursor protein-cleaving enzyme; IL, interleukin; Aβ, amyloid-β; sAPP, soluble N-terminal fragment of amyloid precursor protein; AD, Alzheimer’s disease.

Table 3 Identified BACE1 substrate-cleavage sites

Substrate	Cleavage site	Reference
APP wild type	SEVKM671 ↓ D672AEFR	66
APP Swedish mutant	SEVNL671 ↓ D672AEFR	66
APLP-2	IDETL659 ↓ D660VKEM	175
Nrg1 type Iβ1	LGIEF237 ↓ M238EAEE	149
PSGL-1	ISVKQ335 ↓ A336ASNL	185
VGSC β2	HLQVL147 ↓ M148EEPP	164
IL1-R2	NTLSF329 ↓ Q330TLRT	186

Abbreviations: BACE-1, β-site amyloid precursor protein-cleaving enzyme; APP, amyloid precursor protein; APLP, amyloid precursor-like protein; Nrg, neuregulin; PSGL, P-selectin glycoprotein ligand-1; VGSC, voltage-gated sodium channel; IL1-R2, interleukin-1 receptor 2.

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