Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF

Abstract

β-amyloid precursor protein (APP) and amyloid beta peptide (Aβ) are strongly implicated in Alzheimer's disease (AD) pathogenesis, although recent evidence has linked APP-βCTF generated by BACE1 (β-APP cleaving enzyme 1) to the development of endocytic abnormalities and cholinergic neurodegeneration in early AD. We show that partial BACE1 genetic reduction prevents these AD-related pathological features in the Ts2 mouse model of Down syndrome (DS). Partially reducing BACE1 by deleting one BACE1 allele blocked development of age-related endosome enlargement in the medial septal nucleus (MSN), cerebral cortex, and hippocampus and loss of choline acetyltransferase (ChAT)-positive MSN neurons. BACE1 reduction normalized APP-βCTF elevation but did not alter Aβ40 and Aβ42 peptide levels in brain, supporting a critical role in vivo for APP-βCTF in the development of these abnormalities. While ameliorative effects of BACE1 inhibition on β-amyloidosis and synaptic proteins levels have been previously noted in AD mouse models, our results highlight the additional potential value of BACE1 modulation in therapeutic targeting of endocytic dysfunction and cholinergic neurodegeneration in DS and AD.

Autophagosomes cooperate in the degradation of intracellular C‐terminal fragments of the amyloid precursor protein via the MVB/lysosomal pathway

“…In this regard, we showed that Atg5 depletion caused an apparent accumulation of CTFs in perinuclear, enlarged organelles positive to LAMP1, as well as positive to CD63, LAMP2, and cathepsin D, suggesting that a dramatic effect on the maturation of MVBs affected the degradation of CTFs. In contrast, recent studies in murine models of Down syndrome and AD show that C99 accumulates in enlarged early endosomes that contain overactivated Rab5 (67–69), suggesting the intriguing possibility that in those cases a similar mechanism of inter organelle fusion is impaired, although it is not well known whether autophagosomes can fuse to early endosomes (70, 71). Nevertheless, our immunofluorescence analysis to EEA1 showed no apparent differences in the morphology of early endosomes in control and Atg5‐depleted cells.…”

Enhanced generation of intraluminal vesicles in neuronal late endosomes in the brain of a Down syndrome mouse model with endosomal dysfunction

“…It was previously shown that early endosomes are enlarged and that the endosomal pathway is dysfunctional in DS and in mouse models of the disease, including the Ts2 model (Cataldo et al, , ; Jiang et al, ; Kaur et al, ; Kim et al, ). We have previously shown higher level of Rab7 in the brain of Ts2 mice compared to 2N (Kaur et al, ).…”

“…Accordingly, Ts2 mice show a DS‐like phenotype (Jiang et al, ; Kaur et al, ; Levine, Saltzman, Levy, & Ginsberg, ), closely resembling the extensively studied Ts65Dn mouse model, but are more chromosomally stable (Villar et al, ). We have previously demonstrated that while the neuronal endosomal pathology occurs in the brain of Ts2 mice at four months of age (Jiang et al, ), enhanced exosomal release can be detected first at 12 months of age (Gauthier et al, ). Therefore, we investigated Ts2 mice at 12 months of age, demonstrating that they have larger and more abundant MVBs per neuron and higher number of ILVs per MVB when compared to their disomic (2N) controls.…”

“…Down syndrome (DS) is the most common human chromosomal disorder (approximately 1–700 live births in the United States (Parker et al, )) and is caused by full trisomy of chromosome 21 or by mosaicism and partial trisomy of the same chromosome, although less frequently. Among other phenotypical features, DS individuals show mild to moderate intellectual disabilities and an increased risk of developing early onset Alzheimer's disease (AD) (Wisniewski, Wisniewski, & Wen, ), likely due to the presence of an extra copy of the amyloid β precursor protein (APP) gene and the consequent elevation in the levels of the APP carboxyl‐terminal fragments (APP‐CTFs) (Cataldo et al, ; Jiang et al, ; Kim et al, ). Given that APP‐CTFs are mostly processed in the endosomal compartment, in recent years growing emphasis has been placed on the analysis of the endosomal–lysosomal pathway.…”

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

“…There are also several downregulated genes involved in AD/DS pathology normalized in Ts65Dn+ mice, including Bace1 . Although associated with β‐cleavage of APP, leading to greater Aβ and βCTF expression, attenuation of Bace1 levels by MCS may indicate a counterintuitive normalization of APP processing in vulnerable neurons that reflects the importance of steady‐state Aβ and βCTF levels, underscoring the importance of evaluating βCTF expression in DS/AD models (Jiang et al, ). Alternatively, Bace1 deficiency may be considered detrimental, as a loss of Bace1 expression impairs myelination (Hu, Hu, Dai, Trapp, & Yan, ) and causes hippocampal synaptic deficits (Petrus & Lee, ; Wang et al, ; Zhu et al, ), illustrating the need for normative Bace1 levels.…”