Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. Accumulation, aggregation, and deposition of amyloid-␤ (A␤) peptides generated through proteolytic cleavage of amyloid precursor protein (APP) are likely initiating events in the pathogenesis of AD. While A␤ production is accelerated in familial AD, increasing evidence indicates that impaired clearance of A␤ is responsible for late-onset AD. Because A␤ is mainly generated in neurons, these cells are predicted to have the highest risk of encountering A␤ among all cell types in the brain. However, it is still unclear whether they are also involved in A␤ clearance. Here we show that receptor-mediated endocytosis in neurons by the low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in brain A␤ clearance. LRP1 is known to be an endocytic receptor for multiple ligands including A␤. Conditional knock-out of Lrp1 in mouse forebrain neurons leads to increased brain A␤ levels and exacerbated amyloid plaque deposition selectively in the cortex of amyloid model APP/PS1 mice without affecting A␤ production. In vivo microdialysis studies demonstrated that A␤ clearance in brain interstitial fluid is impaired in neuronal Lrp1 knock-out mice. Because the neuronal LRP1-deletion did not affect the mRNA levels of major A␤ degrading enzymes, neprilysin and insulin-degrading enzyme, the disturbed A␤ clearance is likely due to the suppression of LRP1-mediated neuronal A␤ uptake and degradation. Together, our results demonstrate that LRP1 plays an important role in receptormediated clearance of A␤ and indicate that neurons not only produce but also clear A␤.

While the accumulation and aggregation of amyloid-b and tau are central events in the pathogenesis of Alzheimer's disease, there is increasing evidence that cerebrovascular pathology is also abundant in Alzheimer's disease brains. In brain capillaries, endothelial cells are connected closely with one another through transmembrane tight junction proteins forming the blood-brain barrier. Because the blood-brain barrier tightly regulates the exchange of molecules between brain and blood and maintains brain homeostasis, its impairment is increasingly recognized as a critical factor contributing to Alzheimer's disease pathogenesis. However, the pathological relationship between blood-brain barrier properties and Alzheimer's disease progression in the human brain is not fully understood. In this study, we show that the loss of cortical tight junction proteins is a common event in Alzheimer's disease, and is correlated with synaptic degeneration. By quantifying the amounts of major tight junction proteins, claudin-5 and occludin, in 12 brain regions dissected from post-mortem brains of normal ageing (n = 10), pathological ageing (n = 14) and Alzheimer's disease patients (n = 19), we found that they were selectively decreased in cortical areas in Alzheimer's disease. Cortical tight junction proteins were decreased in association with the Braak neurofibrillary tangle stage. There was also a negative correlation between the amount of tight junction proteins and the amounts of insoluble Alzheimer's disease-related proteins, in particular amyloid-b 40 , in cortical areas. In addition, the amount of tight junction proteins in these areas correlated positively with those of synaptic markers. Thus, loss of cortical tight junction proteins in Alzheimer's disease is associated with insoluble amyloid-b 40 and loss of synaptic markers. Importantly, the positive correlation between claudin-5 and synaptic markers, in particular synaptophysin, was present independent of insoluble amyloid-b 40 , amyloid-b 42 and tau values, suggesting that loss of cortical tight junction proteins and synaptic degeneration is present, at least in part, independent of insoluble Alzheimer's disease-related proteins. Collectively, these results indicate that loss of tight junction proteins occurs predominantly in the neocortex during Alzheimer's disease progression. Further, our findings provide a neuropathological clue as to how endothelial tight junction pathology may contribute to Alzheimer's disease pathogenesis in both synergistic and additive manners to typical amyloid-b and tau pathologies.

Objective Apolipoprotein E (apoE), a major cholesterol carrier in the brain, is associated with a strong risk for Alzheimer’s disease. Compared to the risky APOE4 gene allele, the effects of the protective APOE2 gene allele are vastly understudied, and thus, need to be further clarified. Methods We reviewed National Alzheimer’s Coordinating Center (NACC) clinical records and performed preclinical experiments using human apoE-targeted replacement (apoE-TR) mice, which do not show amyloid pathology. Results Clinically, the APOE2 allele was associated with less cognitive decline during aging. This effect was also seen in subjects with little amyloid pathology, or after adjusting for Alzheimer’s disease-related pathologies. In animal studies, aged apoE2-TR mice also exhibited preserved memory function in the water maze tests. Regardless, apoE2-TR mice showed similar or greater age-related changes in synaptic loss, neuroinflammation and oxidative stress compared to apoE3- or apoE4-TR mice. Interestingly, apoE concentrations in the cortex, hippocampus, plasma and cerebrospinal fluid (CSF) were positively correlated with memory performance across apoE isoforms, where apoE2-TR mice had higher apoE levels. Moreover, apoE2-TR mice exhibited the lowest levels of cholesterol in the cortex, in spite of higher levels in CSF and plasma. These cholesterol levels were associated with apoE levels and memory performance across apoE isoforms. Interpretation APOE2 is associated with less cognitive decline during aging. This can occur independently of age-related synaptic/neuroinflammatory changes and amyloid accumulation. Higher levels of apoE and associated cholesterol metabolism in APOE2 carriers might contribute to this protective effect.