Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits

Abstract

Autophagy, a major degradative pathway for proteins and organelles, is essential for survival of mature neurons. Extensive autophagic-lysosomal pathology in Alzheimer's disease brain contributes to Alzheimer's disease pathogenesis, although the underlying mechanisms are not well understood. Here, we identified and characterized marked intraneuronal amyloid-β peptide/amyloid and lysosomal system pathology in the Alzheimer's disease mouse model TgCRND8 similar to that previously described in Alzheimer's disease brains. We further establish that the basis for these pathologies involves defective proteolytic clearance of neuronal autophagic substrates including amyloid-β peptide. To establish the pathogenic significance of these abnormalities, we enhanced lysosomal cathepsin activities and rates of autophagic protein turnover in TgCRND8 mice by genetically deleting cystatin B, an endogenous inhibitor of lysosomal cysteine proteases. Cystatin B deletion rescued autophagic-lysosomal pathology, reduced abnormal accumulations of amyloid-β peptide, ubiquitinated proteins and other autophagic substrates within autolysosomes/lysosomes and reduced intraneuronal amyloid-β peptide. The amelioration of lysosomal function in TgCRND8 markedly decreased extracellular amyloid deposition and total brain amyloid-β peptide 40 and 42 levels, and prevented the development of deficits of learning and memory in fear conditioning and olfactory habituation tests. Our findings support the pathogenic significance of autophagic-lysosomal dysfunction in Alzheimer's disease and indicate the potential value of restoring normal autophagy as an innovative therapeutic strategy for Alzheimer's disease.

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

“…Because BACE1 is normally abundantly localized to axons (34) and is degraded by lysosomes (15,38,39), our observations suggest that cathepsin levels might be rate-limiting for the efficient degradation of BACE1 and thus lead to its high abundance at such sites. This concept is supported by previous studies that detected reductions in amyloid plaque burden after the enhancement of cathepsin activity in mouse models of AD (67)(68)(69). Although such studies largely focused on cathepsin-mediated Aβ peptide degradation as a mechanism for explaining the overall reduction in Aβ levels and amyloid plaque load, the possibility that elevated cathepsin levels/activity exerted additional antiamyloidogenic effects via enhanced BACE1 breakdown requires further investigation in light of our new findings.…”

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

“…Autophagy is a basic cellular catabolic mechanism, through which the unnecessary or dysfunctional cellular proteins and organelle components are degraded through the lysosomal machinery (52). Growing evidence has shown that autophagy is impaired in AD (53)(54)(55). Histological analysis shows accumulation of autophagosomes and autolysosomes in neurons of AD brains (56).…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…The genetic deletion of an endogenous inhibitor of cathepsins, cystatin B, ameliorates the memory deficits and Aβ aggregate load in a mouse model of AD 153 , which indicates that lysosomal proteases are able to clear diseasecausing proteins in AD and that their upregulation should be beneficial (Suppl Table S4). In HD, it was proposed that the expression of mHtt impairs vesicular transport from the Golgi to the lysosomes and thus leads to a reduction in lysosomal cathepsins 154 (Figure 5), which would result in inefficient autophagy in HD.…”

“…Reduced BDNF levels 39,40 Increasing BDNF & NGF levels is beneficial in disease models [51][52][53][54] Increased p75 NTR levels and signalling 75,172 Decreased Trk receptor levels and signalling 75,172 Increased Gsk3ß activity 66,173 Altered ERK activity 174 Reduced velocity and efficiency of axonal transport of BDNF 65,66 Apoptotic pathways Increased caspase-6 activity 89,90 Caspase-6 cleavage of disease proteins [89][90][91][92] Preventing caspase cleavage of disease proteins is beneficial in mouse models 93,94 Posttranslational modifications Palmitoylation of disease proteins is linked to aggregate formation 118,119 Phosphorylation of disease proteins reduces their cleavage by caspases 105,106 HDAC inhibition is beneficial in disease models 69,126,127 Protein aggregation and clearance mechanisms Misfolding and aggregation of disease proteins 128 UPS impairment 144,145 Impaired autophagy 161 Upregulation of autophagy is beneficial in disease models 153,155,156,158,162,163,165,167,<...>…”