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Abstract Background Neuroinflammation and Alzheimer’s disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology. Methods The morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis. Results Morphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases. Conclusions In conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD.

Well-characterized, high-quality brain tissue of non-neurological control subjects is a prerequisite to study the healthy aging brain, and can serve as a control for the study of neurological disorders. The Normal Aging Brain Collection Amsterdam (NABCA) provides a comprehensive collection of post-mortem (ultra-)high-field MRI (3Tesla and 7 Tesla) and neuropathological datasets of non-neurological controls. By providing MRI within the pipeline, NABCA uniquely stimulates translational neurosciences; from molecular and morphometric tissue studies to the clinical setting. We describe our pipeline, including a description of our on-call autopsy team, donor selection, in situ and ex vivo post-mortem MRI protocols, brain dissection and neuropathological diagnosis. A demographic, radiological and pathological overview of five selected cases on all these aspects is provided. Additionally, information is given on data management, data and tissue application procedures, including review by a scientific advisory board, and setting up a material transfer agreement before distribution of tissue. Finally, we focus on future prospects, which includes laying the foundation for a unique platform for neuroanatomical, histopathological and neuro-radiological education, of professionals, students and the general (lay) audience. Keywords: Brain banking, Non-neurological controls, MRI, Neuropathology

In a comprehensive proteomics study aiming at the identification of proteins associated with amyloid-beta (Aβ)-mediated toxicity in cultured cortical neurons, we have identified Thimet oligopeptidase (THOP1). Functional modulation of THOP1 levels in primary cortical neurons demonstrated that its overexpression was neuroprotective against Aβ toxicity, while RNAi knockdown made neurons more vulnerable to amyloid peptide. In the TgCRND8 transgenic mouse model of amyloid plaque deposition, an age-dependent increase of THOP1 expression was found in brain tissue, where it co-localized with Aβ plaques. In accordance with these findings, THOP1 expression was significantly increased in human AD brain tissue as compared to non-demented controls. These results provide compelling evidence for a neuroprotective role of THOP1 against toxic effects of Aβ in the early stages of AD pathology, and suggest that the observed increase in THOP1 expression might be part of a compensatory defense mechanism of the brain against an increased Aβ load.

In Alzheimer's disease (AD) brain, increased levels of cyclooxygenase-2 (COX-2), cell cycle markers, and p38 MAP kinase (MAPK) can be detected in neuronal cells. Besides mediating COX-2 expression, p38 MAPK is suggested to mediate cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In this study, we show that neuronal immunoreactivity for phosphorylated p38 MAPK does not correlate with COX-2 or phosphorylated pRb (ppRb) in control and AD temporal cortex. Immunoreactivity for activated p38 MAPK co-localizes with AT8 immunoreactivity and increases with the occurrence of neurofibrillary tangles and plaques. On the other hand, COX-2 immunoreactivity co-localizes and correlates with ppRb immunoreactivity in pyramidal neurons. COX-2 and ppRb do not co-localize with AT8 and decrease with increasing pathology. These results suggest that p38 MAPK does not mediate COX-2 expression and pRb inactivation, which are involved in cellular changes in pyramidal neurons early in AD pathogenesis.