Tags

Type your tag names separated by a space and hit enter

A combination Alzheimer's therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice.
Mol Brain. 2015 Mar 25; 8:19.MB

Abstract

BACKGROUND

Accumulating evidence indicates that partial inhibition of β-site APP-cleaving enzyme 1 (BACE1), which initiates amyloid-β (Aβ) production, mitigates Alzheimer's disease (AD)-like pathologies and memory deficits in a battery of transgenic mouse models. However, our previous investigations suggest that therapeutic BACE1 suppression may be beneficial only if targeted on earlier stages of AD and encounter dramatic reductions in efficacy during disease progression. This study was designed to test the possibility that a combination approach, aimed at inhibiting BACE1 and boosting neprilysin (a major Aβ-degrading enzyme) activities, may be able to mechanistically overcome the limited efficacy of anti-Aβ therapy in advanced AD.

RESULTS

After crossbreeding between BACE1 heterozygous knockout (BACE1(+/-)), neprilysin transgenic (NEP) and 5XFAD mice, we analyzed the resultant mice at 12 months of age when 5XFAD controls showed robust amyloid-β (Aβ) accumulation and elevation of BACE1 expression (~2 folds). Although haploinsufficiency lowered BACE1 expression by ~50% in concordance with reduction in gene copy number, profound β-amyloidosis, memory deficits and cholinergic neuron death were no longer rescued in BACE1(+/-) · 5XFAD mice concomitant with their persistently upregulated BACE1 (i.e., equivalent to wild-type control levels). Notably, neprilysin overexpression not only prevented Aβ accumulation but also suppressed the translation initiation factor eIF2α-associated elevation of BACE1 and lowered levels of the β-secretase-cleaved C-terminal fragment of APP (C99) in NEP · 5XFAD mice. Interestingly, these markers for β-amyloidogenesis in BACE1(+/-) · NEP · 5XFAD mice were further reduced to the levels reflecting a combination of single BACE1 allele ablation and the abolishment of translational BACE1 upregulation. However, since neprilysin overexpression was striking (~8-fold relative to wild-type controls), memory impairments, cholinergic neuronal loss and β-amyloidosis were similarly prevented in NEP · 5XFAD and BACE1(+/-) · NEP · 5XFAD mice.

CONCLUSIONS

Our findings indicate that robust overexpression of neprilysin is sufficient to ameliorate AD-like phenotypes in aged 5XFAD mice. We also found that Aβ-degrading effects of overexpressed neprilysin can block deleterious BACE1-elevating mechanisms that accelerate Aβ production, warranting further study to test whether interventions moderately activating neprilysin may be useful for boosting the limited efficacy of therapeutic BACE1 inhibition in treating AD with established Aβ pathology.

Authors+Show Affiliations

Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY, 10962, USA. ldevi@nki.rfmh.org.Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY, 10962, USA. mohno@nki.rfmh.org. Department of Psychiatry, New York University Langone Medical Center, New York, NY, 10016, USA. mohno@nki.rfmh.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25884928

Citation

Devi, Latha, and Masuo Ohno. "A Combination Alzheimer's Therapy Targeting BACE1 and Neprilysin in 5XFAD Transgenic Mice." Molecular Brain, vol. 8, 2015, p. 19.
Devi L, Ohno M. A combination Alzheimer's therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice. Mol Brain. 2015;8:19.
Devi, L., & Ohno, M. (2015). A combination Alzheimer's therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice. Molecular Brain, 8, 19. https://doi.org/10.1186/s13041-015-0110-5
Devi L, Ohno M. A Combination Alzheimer's Therapy Targeting BACE1 and Neprilysin in 5XFAD Transgenic Mice. Mol Brain. 2015 Mar 25;8:19. PubMed PMID: 25884928.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A combination Alzheimer's therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice. AU - Devi,Latha, AU - Ohno,Masuo, Y1 - 2015/03/25/ PY - 2015/01/30/received PY - 2015/03/11/accepted PY - 2015/4/18/entrez PY - 2015/4/18/pubmed PY - 2016/1/20/medline SP - 19 EP - 19 JF - Molecular brain JO - Mol Brain VL - 8 N2 - BACKGROUND: Accumulating evidence indicates that partial inhibition of β-site APP-cleaving enzyme 1 (BACE1), which initiates amyloid-β (Aβ) production, mitigates Alzheimer's disease (AD)-like pathologies and memory deficits in a battery of transgenic mouse models. However, our previous investigations suggest that therapeutic BACE1 suppression may be beneficial only if targeted on earlier stages of AD and encounter dramatic reductions in efficacy during disease progression. This study was designed to test the possibility that a combination approach, aimed at inhibiting BACE1 and boosting neprilysin (a major Aβ-degrading enzyme) activities, may be able to mechanistically overcome the limited efficacy of anti-Aβ therapy in advanced AD. RESULTS: After crossbreeding between BACE1 heterozygous knockout (BACE1(+/-)), neprilysin transgenic (NEP) and 5XFAD mice, we analyzed the resultant mice at 12 months of age when 5XFAD controls showed robust amyloid-β (Aβ) accumulation and elevation of BACE1 expression (~2 folds). Although haploinsufficiency lowered BACE1 expression by ~50% in concordance with reduction in gene copy number, profound β-amyloidosis, memory deficits and cholinergic neuron death were no longer rescued in BACE1(+/-) · 5XFAD mice concomitant with their persistently upregulated BACE1 (i.e., equivalent to wild-type control levels). Notably, neprilysin overexpression not only prevented Aβ accumulation but also suppressed the translation initiation factor eIF2α-associated elevation of BACE1 and lowered levels of the β-secretase-cleaved C-terminal fragment of APP (C99) in NEP · 5XFAD mice. Interestingly, these markers for β-amyloidogenesis in BACE1(+/-) · NEP · 5XFAD mice were further reduced to the levels reflecting a combination of single BACE1 allele ablation and the abolishment of translational BACE1 upregulation. However, since neprilysin overexpression was striking (~8-fold relative to wild-type controls), memory impairments, cholinergic neuronal loss and β-amyloidosis were similarly prevented in NEP · 5XFAD and BACE1(+/-) · NEP · 5XFAD mice. CONCLUSIONS: Our findings indicate that robust overexpression of neprilysin is sufficient to ameliorate AD-like phenotypes in aged 5XFAD mice. We also found that Aβ-degrading effects of overexpressed neprilysin can block deleterious BACE1-elevating mechanisms that accelerate Aβ production, warranting further study to test whether interventions moderately activating neprilysin may be useful for boosting the limited efficacy of therapeutic BACE1 inhibition in treating AD with established Aβ pathology. SN - 1756-6606 UR - https://www.unboundmedicine.com/medline/citation/25884928/A_combination_Alzheimer's_therapy_targeting_BACE1_and_neprilysin_in_5XFAD_transgenic_mice_ L2 - https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-015-0110-5 DB - PRIME DP - Unbound Medicine ER -