Quantitative in vivo assessment of amyloid-beta phagocytic capacity in an Alzheimer's disease mouse model.

Alzheimer's disease is characterized by the deposition of extracellular amyloid-beta (Aß) plaques. While microglial phagocytosis is a major mechanism through which Aß is cleared, there is no method for quantitatively assessing Aß phagocytic capacity of microglia in vivo. Here, we present a flow cytometry-based method for investigating the Aß phagocytic capacity of microglia in vivo. This method enables the direct comparison of Aß phagocytic capacity between different microglial subpopulations as well as the direct isolation of Aß phagocytic microglia for downstream applications. For complete details on the use and execution of this protocol, please refer to Lau et al. (2020).

Alzheimer's disease plaques and tangles: cemeteries of a pyrrhic victory of the immune defence network against herpes simplex infection at the expense of complement and inflammation-mediated neuronal destruction.

Plaques and tangles are highly and significantly enriched in herpes simplex (HSV-1) binding proteins (by 11 and 15 fold respectively (P<4.47466E-39) and 132/341 (39%) of the known HSV-1 binding partners or associates are present in these structures. The classes involved include the majority (63-100%) of the known HSV-1 host protein carriers and receptors, 85-91% of the viral associated proteins involved in endocytosis, intracellular transport and exocytosis and 71% of the host proteins associated with the HSV-1 virion. The viral associated proteins found in plaques or tangles trace out a complete itinerary of the virus from entry to exocytosis and the virus also binds to plaque or tangle components involved in apoptosis, DNA transcription, translation initiation, protein chaperoning, the ubiquitin/proteasome system and the immune network. Along this route, the virus deletes mitochondrial DNA, as seen in Alzheimer's disease, sequesters the neuroprotective peptide, ADNP, and interferes with key proteins related to amyloid precursor protein processing and signalling as well as beta-amyloid processing, microtubule stability and tau phosphorylation, the core pathologies of Alzheimer's disease. Amyloid-containing plaques or neurofibrillary tangles also contain a large number of complement, acute phase and immune-related proteins, and the presence of these pathogen defence related classes along with HSV-1 binding proteins suggests that amyloid plaques and tangles represent cemeteries for a battle between the virus and the host's defence network. The presence of the complement membrane attack complex in Alzheimer's disease neurones suggests that complement mediated neuronal lysis may be a consequence of this struggle. HSV-1 infection is known to increase beta-amyloid deposition and tau phosphorylation and also results in cortical and hippocampal neuronal loss, cerebral shrinkage and memory deficits in mice. This survey supports the contention that herpes simplex viral infection contributes to Alzheimer's disease, in genetically predisposed individuals. Genetic conditioning effects are likely to be important, as all of the major risk promoting genes in Alzheimer's disease (apolipoprotein E, clusterin, complement receptor 1 and the phosphatidylinositol binding clathrin assembly protein PICALM), and many lesser susceptibility genes, are related to the herpes simplex life cycle. 33 susceptibility genes are related to the immune system. Vaccination or antiviral agents and immune suppressants should therefore perhaps be considered as viable therapeutic options, prior to, or in the early stages of Alzheimer's disease.

IV immunoglobulin is associated with a reduced risk of Alzheimer disease and related disorders.

OBJECTIVE: To compare the incidence of Alzheimer disease and related disorders (ADRD) in patients treated with IV immunoglobulin (IVIg) for non-Alzheimer disease (AD) indications vs untreated controls. METHODS: This retrospective case-control analysis used medical claims for patients > or =65 years old from a national database of 20 million age-qualified patients. Cases received > or =1 IVIg administration during April 1, 2001-August 31, 2004, had claims 1 year prior to first (index) IVIg administration to confirm absence of pre-index ADRD, and had > or =3 years of continuous claims post-index. Untreated controls had their first medical claim during April 1, 2000-August 31, 2004, and otherwise met the same requirements as cases. Controls were matched 100:1 to cases on age, gender, and risk factors for ADRD. The relative incidence of ADRD post-index for the IVIg-treated cases vs untreated controls was estimated using Kaplan-Meier survival curves and a Cox proportional hazards model. RESULTS: Treated patients in the Kaplan-Meier analysis had lower ADRD incidence (p = 0.02) with an estimated 2.6% of the 847 IVIg-treated vs 4.6% of 84,700 controls diagnosed with ADRD at 60 months after index date. Treated patients in the Cox proportional hazard model had a 42% lower risk of being diagnosed with ADRD (hazard ratio, 0.577; 95% confidence interval, 0.359 to 0.930; p = 0.024) with an estimated 2.8% of treated vs 4.8% of controls diagnosed with ADRD at 60 months after index date. CONCLUSIONS: Previous treatment with IV immunoglobulin was associated with a reduced risk of developing Alzheimer disease and related disorders (ADRD) in this study. Evidence from additional studies is needed to evaluate the relationship between IVIg exposure and ADRD diagnosis.