Centrally Delivered BACE1 Inhibitor Activates Microglia, and Reverses Amyloid Pathology and Cognitive Deficit in Aged Tg2576 Mice.
Multiple small-molecule inhibitors of the β-secretase enzyme (BACE1) are under preclinical or clinical investigation for Alzheimer's disease (AD). Prior work has illustrated robust lowering of central amyloid β (Aβ) after acute administration of BACE1 inhibitors. However, very few studies have assessed the overall impact of chronically administered BACE1 inhibitors on brain amyloid burden, neuropathology, and behavioral function in aged preclinical models. We investigated the effects of a potent nonbrain-penetrant BACE1 inhibitor, delivered directly to the brain using intracerebroventricular infusion in an aged transgenic mouse model. Intracerebroventricular infusion of the BACE1 inhibitor (0.3-23.5 μg/d) for 8 weeks, initiated in 17-month-old Tg2576 mice, produced dose-dependent increases in brain inhibitor concentrations (0.2-13 μm). BACE1 inhibition significantly reversed the behavioral deficit in contextual fear conditioning, and reduced brain Aβ levels, plaque burden, and associated pathology (e.g., dystrophic neurites), with maximal effects attained with ∼1 μg/d dose. Strikingly, the BACE1 inhibitor also reversed amyloid pathology below baseline levels (amyloid burden at the start of treatment), without adversely affecting cerebral amyloid angiopathy, microhemorrhages, myelination, or neuromuscular function. Inhibitor-mediated decline in brain amyloid pathology was associated with an increase in microglial ramification. This is the first demonstration of chronically administered BACE1 inhibitor to activate microglia, reverse brain amyloid pathology, and elicit functional improvement in an aged transgenic mouse model. Thus, engagement of novel glial-mediated clearance mechanisms may drive disease-modifying therapeutic benefit with BACE1 inhibition in AD.
Neuromodulation Global Research, Technology & Development.
Deepak R
DR
Thakker
Neuroscience.
Sethu
S
Sankaranarayanan
Strategy & Scientific Operations, Medtronic, Minneapolis, Minnesota 55432-5604, and.
Marcy R
http://orcid.org/0000-0003-4744-201X
MR
Weatherspoon
Neuromodulation Global Research, Technology & Development.
Jonathan
http://orcid.org/0000-0003-4895-7402
J
Harrison
Neuroscience.
Maria
M
Pierdomenico
Neuromodulation Global Research, Technology & Development.
Jennifer M
JM
Heisel
Chemistry.
Lorin A
LA
Thompson
Pharmaceutics, and.
Roy
R
Haskell
Metabolism & Pharmacokinetics, Bristol-Myers Squibb, Wallingford, Connecticut 06492.
James E
http://orcid.org/0000-0003-4931-4273
JE
Grace
Metabolism & Pharmacokinetics, Bristol-Myers Squibb, Wallingford, Connecticut 06492.
Sarah J
SJ
Taylor
Neuroscience.
Charles F
CF
Albright
Neuromodulation Global Research, Technology & Development, lisa.shafer@upsher-smith.com.
Lisa L
http://orcid.org/0000-0002-3751-2216
LL
Shafer
D000367:Age Factors; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005239:Fear / Q000187:drug effects; D006801:Humans; D057967:Infusions, Intraventricular; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000473:pathology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse