Central and Peripheral Administration of Antisense Oligonucleotide Targeting Amyloid-β Protein Precursor Improves Learning and Memory and Reduces Neuroinflammatory Cytokines in Tg2576 (AβPPswe) Mice

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. The World Health Organization estimates that there are currently 18 million people worldwide living with AD and that number is expected to double by early 2025. Currently, there are no therapies to stop or reverse the symptoms of AD. We have developed an antisense oligonucleotide (OL-1) against the amyloid betaprotein precursor (AβPP) that can decrease AβPP expression and amyloid beta protein (Aβ) production. This antisense rapidly crosses the blood-brain barrier, reverses learning and memory impairments, reduces oxidative stress and restores brain-to-blood efflux of Aβ in SAMP8 mice. In the current study, we examined the effects of this AβPP antisense in the Tg2576 mouse model of AD. The Tg2576 overproduces human Aβ, develops age-related learning and memory deficits, and exhibits oxidative damage in the brain. First, we administered the AβPP antisense centrally into the lateral ventricle 3 times at 2 week intervals. Seventy-two hours after the third injection, we tested learning and memory in T-maze foot shock avoidance. In the second study, we injected the mice with AβPP antisense 3 times at two week intervals via the tail vein. Seventy-two hours later, we tested learning and memory T-maze foot shock avoidance, novel object recognition and elevated plus maze. At the end of behavioral testing, mice were sacrificed and brain tissue was collected for evaluation of AβPP, Aβ, and expression of cytokines and chemokines. AβPP antisense administered centrally improved acquisition and retention of T-maze foot shock avoidance. AβPP antisense administered via tail vein improved learning and memory in both T-maze foot shock avoidance and novel object-place recognition. In the elevated plus maze the mice which received OL-1 AβPP antisense spent less time in the open arms and had fewer entries into the open arms indicating reduced disinhibitation. Biochemical analyses reveal significant reduction of AβPP signal and a reduction of measures of neuroinflammation. The current findings support the therapeutic potential of OL-1 AβPP antisense.

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

“…SAMP8 mice were subjected to object recognition testing to determine the effects that intranasal insulin administration had on changes to declarative memory as previously described [26, 27]. Briefly, SAMP8 mice were habituated to an empty apparatus prior to training.…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Thus, therapeutic strategies for AD, PD, and FTD might require reducing the synthesis, preventing the aggregation and/or enhancing the clearance of Aβ, tau, or α-syn. Numerous strategies directed at reducing the accumulation of these proteins have been developed, including the use of small interfering RNA, antisense RNA [39][40][41][42][43], degrading enzymes (e.g., cathepsin D, neurosin, neprilysin) [44][45][46], chaperonelike molecules that modulate aggregation state (e.g., Hsp70, β-syn) [47][48][49][50], anti-aggregation compounds (e.g., polyphenols) [51][52][53], and immunotherapy (passive, active, and Tcell-based) [54]. Moreover, the recent discovery that toxic oligomeric forms of α-syn and tau accumulate in the plasma membrane and are secreted to the extracellular environment has provided further rationale for the development of immunotherapeutic approaches for PD, DLB, MSA, FTD, and other neurodegenerative disorders characterized by the abnormal accumulation of these proteins [24,26,[55][56][57][58].…”

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

“…Allele-specific APP downregulation using short interfering RNA improved behavior in an Alzheimer mouse model carrying the Swedish mutation (Rodriguez-Lebron et al, 2009). Using the same model, central and peripheral administration of an antisense oligonucleotide targeting APP, reduced formation of Aβ, and improved the AD phenotype (Farr et al, 2014). However, APP has multiple morphoregulatory functions, like regulation of neurite outgrowth, and complete knockdown of APP expression could lead to major side effects (Gralle and Ferreira, 2007).…”