Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice.

ß-Site APP (amyloid precursor protein) cleaving enzyme 1 (BACE1) is the ß-secretase enzyme that initiates production of the toxic amyloid-ß peptide that accumulates in the brains of patients with Alzheimer's disease (AD). Hence, BACE1 is a prime therapeutic target, and several BACE1 inhibitor drugs are currently being tested in clinical trials for AD. However, the safety of BACE1 inhibition is unclear. Germline BACE1 knockout mice have multiple neurological phenotypes, although these could arise from BACE1 deficiency during development. To address this question, we report that tamoxifen-inducible conditional BACE1 knockout mice in which the Bace1 gene was ablated in the adult largely lacked the phenotypes observed in germline BACE1 knockout mice. However, one BACE1-null phenotype was induced after Bace1 gene deletion in the adult mouse brain. This phenotype showed reduced length and disorganization of the hippocampal mossy fiber infrapyramidal bundle, the axonal pathway of dentate gyrus granule cells that is maintained by neurogenesis in the mouse brain. This defect in axonal organization correlated with reduced BACE1-mediated cleavage of the neural cell adhesion protein close homolog of L1 (CHL1), which has previously been associated with axon guidance. Although our results indicate that BACE1 inhibition in the adult mouse brain may avoid phenotypes associated with BACE1 deficiency during embryonic and postnatal development, they also suggest that BACE1 inhibitor drugs developed for treating AD may disrupt the organization of an axonal pathway in the hippocampus, an important structure for learning and memory.

Intensive 'Brain Training' Intervention Fails to Reduce Amyloid Pathologies or Cognitive Deficits in Transgenic Mouse Models of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-ß protein (Aß) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field. One controversial strategy, cognitive-specific stimulation, has been studied previously in human participants and has been widely commercialized in the form of 'brain-training games.' In the present study, we developed a highly controlled, isolated cognitive training intervention program for mice. Two transgenic mouse lines, one that develops Aß deposition largely in brain parenchyma, and another in the cerebral microvasculature, progressed through a series of domain-specific tasks for an average of 4 months. Despite the high intensity and duration of the intervention, we found little evidence of positive benefits for AD amyloid pathologies and post-training cognitive testing in these two models. Taken together, these results support the current evidence in human studies that cognitive-specific stimulation does not lead to a measurable reduction in AD pathology or an improvement in general brain health.

N-terminal region of myelin basic protein reduces fibrillar amyloid-ß deposition in Tg-5xFAD mice.

Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by extensive deposition of fibrillar amyloid-ß (Aß) in the brain. Previously, myelin basic protein (MBP) was identified to be a potent inhibitor to Aß fibril formation, and this inhibitory activity was localized to the N-terminal residues 1-64, a fragment designated MBP1. Here, we show that the modest neuronal expression of a fusion protein of the biologically active MBP1 fragment and the enhanced green fluorescent protein (MBP1-EGFP) significantly improved the performance of spatial learning memory in Tg-5xFAD mice, a model of pathologic Aß accumulation in brain. The levels of insoluble Aß and fibrillar amyloid were significantly reduced in bigenic Tg-5xFAD/Tg-MBP1-EGFP mice. Quantitative stereological analysis revealed that the reduction in amyloid was because of a reduction in the size of fibrillar plaques rather than a decrease in plaque numbers. The current findings support previous studies showing that MBP1 inhibits Aß fibril formation in vitro and demonstrate the ability of MBP1 to reduce Aß pathology and improve behavioral performance.

Early-onset formation of parenchymal plaque amyloid abrogates cerebral microvascular amyloid accumulation in transgenic mice.

The fibrillar assembly and deposition of amyloid ß (Aß) protein, a key pathology of Alzheimer disease, can occur in the form of parenchymal amyloid plaques and cerebral amyloid angiopathy (CAA). Familial forms of CAA exist in the absence of appreciable parenchymal amyloid pathology. The molecular interplay between parenchymal amyloid plaques and CAA is unclear. Here we investigated how early-onset parenchymal amyloid plaques impact the development of microvascular amyloid in transgenic mice. Tg-5xFAD mice, which produce non-mutated human Aß and develop early-onset parenchymal amyloid plaques, were bred to Tg-SwDI mice, which produce familial CAA mutant human Aß and develop cerebral microvascular amyloid. The bigenic mice presented with an elevated accumulation of Aß and fibrillar amyloid in the brain compared with either single transgenic line. Tg-SwDI/Tg-5xFAD mice were devoid of microvascular amyloid, the prominent pathology of Tg-SwDI mice, but exhibited larger parenchymal amyloid plaques compared with Tg-5xFAD mice. The larger parenchymal amyloid deposits were associated with a higher loss of cortical neurons and elevated activated microglia in the bigenic Tg-SwDI/Tg-5xFAD mice. The periphery of parenchymal amyloid plaques was largely composed of CAA mutant Aß. Non-mutated Aß fibril seeds promoted CAA mutant Aß fibril formation in vitro. Further, intrahippocampal administration of biotin-labeled CAA mutant Aß peptide accumulated on and adjacent to pre-existing parenchymal amyloid plaques in Tg-5xFAD mice. These findings indicate that early-onset parenchymal amyloid plaques can serve as a scaffold to capture CAA mutant Aß peptides and prevent their accumulation in cerebral microvessels.

The absence of myelin basic protein promotes neuroinflammation and reduces amyloid ß-protein accumulation in Tg-5xFAD mice.

BACKGROUND: Abnormal accumulation of amyloid ß-protein (Aß) in the brain plays an important role in the pathogenesis \of Alzheimer's disease (AD). Aß monomers assemble into oligomers and fibrils that promote neuronal dysfunction. This assembly pathway is influenced by naturally occurring brain molecules, the Aß chaperone proteins, which bind to Aß and modulate its aggregation. Myelin basic protein (MBP) was previously identified as a novel Aß chaperone protein and a potent inhibitor for Aß fibril assembly in vitro. METHODS: In this study, we determined whether the absence of MBP would influence Aß pathology in vivo by breeding MBP knockout mice (MBP-/-) with Tg-5xFAD mice, a model of AD-like parenchymal Aß pathology. RESULTS: Through biochemical and immunohistochemical experiments, we found that bigenic Tg-5xFAD/MBP-/- mice had a significant decrease of insoluble Aß and parenchymal plaque deposition at an early age. The expression of transgene encoded human AßPP, the levels of C-terminal fragments generated during Aß production and the intracellular Aß were unaffected in the absence of MBP. Likewise, we did not find a significant difference in plasma Aß or cerebrospinal fluid Aß, suggesting these clearance routes were unaltered in bigenic Tg-5xFAD/MBP-/- mice. However, MBP-/- mice and bigenic Tg-5xFAD/MBP-/- mice exhibited elevated reactive astrocytes and activated microglia compared with Tg-5xFAD mice. The Aß degrading enzyme matrix metalloproteinase 9 (MMP-9), which is expressed by activated glial cells, was significantly increased in the Tg-5xFAD/MBP-/- mice. CONCLUSIONS: These findings indicate that the absence of MBP decreases Aß deposition in transgenic mice and that this consequence may result from increased glial activation and expression of MMP-9, an Aß degrading enzyme.