Cristina d'Abramo’s research while affiliated with Feinstein Institute for Medical Research and other places

Plasma levels of protein biomarkers glial fibrillary acidic protein (GFAP) and neurofilament light (NEFL) are key dementia biomarkers, but it is unclear how risk genes for Alzheimer s disease (AD) influence levels of these biomarkers. We investigated the association of the established high-effect variants for AD in APOE and TREM2 with these biomarkers, using data from over 50,000 participants from the UK Biobank (UKB). The results show that APOE4 is associated with elevated levels of plasma GFAP, and to a lesser extent, NEFL. The APOE4 effect on GFAP increases with age and the number of APOE4 alleles. The risk variants R47H and R62H in TREM2 are associated with higher NEFL levels, but not with GFAP, and the effect sizes do not increase with age. Higher levels of both GFAP and NEFL in midlife are significantly associated with greater risk for incident dementia. In contrast, the protective APOE2 allele showed no effect on GFAP or NEFL. In conclusion, we find that major genetic risk factors for AD differentially affect dementia protein biomarkers across age, indicating gene specific pathways with potential therapeutic implications.

Tau is a primary target for immunotherapy in Alzheimer’s disease. Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels in vitro and in vivo . Here, we compared the effects of single-chain variable fragments (scFv) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used adeno-associated virus 1 (AAV1) to deliver scFvs to skeletal muscle cells in eight-week-old P301S tau transgenic mice. We evaluated motor and behavioral functions at 16 and 23 weeks of age and measured misfolded, soluble, oligomeric and insoluble brain tau species. Monotherapy with scFv-MC1 improved motor and behavioral functions more effectively than scFv-PHF1 or combination therapy. Brain glucose metabolism also benefited from scFv-MC1 treatment. Surprisingly, combining scFvs targeting early (MC1) and late (PHF1) tau modifications did not produce additive or synergistic effects. These results confirm that intramuscular AAV1-mediated scFv-MC1 gene therapy holds promise as a potential treatment for Alzheimer’s disease. Our findings also suggest that combining scFvs targeting different tau epitopes may not necessarily enhance efficacy if administered together in a prevention paradigm. Further research is needed to explore whether other antibodies’ combinations and/or administration schedules could improve the efficacy of scFv-MC1 alone. Graphical abstract/eTOC synopsis Katel and colleagues show that peripheral vectorized scFvMC1 (in monotherapy) reduces pathological tau species in tau transgenic mice more efficiently than in combination with scFv-PHF1. The authors observed improved motor and behavioral functions together with increased brain glucose metabolism in scFv-MC1-treated mice.

APOE is a major genetic factor in late-onset Alzheimer’s disease (LOAD), with APOE4 increasing risk, APOE3 acting as neutral, and APOE2 offering protection. APOE also plays key role in lipid metabolism, affecting both peripheral and central systems, particularly in lipoprotein metabolism in triglyceride and cholesterol regulation. APOE2 is linked to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia due to impaired binding to Low-Density Lipoproteins receptors. To explore the impact of human APOE isoforms on LOAD and lipid metabolism, we developed Long-Evans rats with human APOE2, APOE3, or APOE4 in place of rat Apoe. These rats were crossed with those carrying a humanized App allele to express human Aβ, which is more aggregation-prone than rodent Aβ, enabling the study of human APOE-human Aβ interactions. In this study, we focused on 80-day-old adolescent rats to analyze early changes that may be associated with the later development of LOAD. We found that APOE2hAβ rats had the highest levels of APOE in serum and brain, with no significant transcriptional differences among isoforms, suggesting variations in protein translation or stability. Aβ43 levels were significantly higher in male APOE4hAβ rats compared to APOE2hAβ rats. However, no differences in Tau or phosphorylated Tau levels were observed across the APOE isoforms. Neuroinflammation analysis revealed lower levels of IL13, IL4 and IL5 in APOE2hAβ males compared to APOE4hAβ males. Neuronal transmission and plasticity tests using field Input-Output (I/O) and long-term potentiation (LTP) recordings showed increased excitability in all APOE-carrying rats, with LTP deficits in APOE2hAβand APOE4hAβ rats compared to ApoehAβ and APOE3hAβ rats. Additionally, a lipidomic analysis of 222 lipid molecular species in serum samples showed that APOE2hAβ rats displayed elevated triglycerides and cholesterol, making them a valuable model for studying HLP. These rats also exhibited elevated levels of phosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine. Minimal differences in lipid profiles between APOE3hAβ and APOE4hAβ rats reflect findings from mouse models. Future studies will include comprehensive lipidomic analyses in various CNS regions and at older ages to further validate these models and explore the effects of APOE isoforms on lipid metabolism in relation to AD pathology. Supplementary Information The online version contains supplementary material available at 10.1186/s12964-024-01832-2.

Background The role of the immune system in responding to neurodegenerative pathology is well established. Microglia are at the center of such response, conveying on one end a positive protective effect, but on the other end, as with senescence, contributing to the hyperinflammation that is a core feature of neurodegeneration. We have identified the transcription factor interferon regulatory factor 5 (IRF5) as a mediator of microglia activation in response to pathological tau, described its specific activation by human‐derived PHF tau and its over‐representation in AD brains. We are now proposing that IRF5 can control the phagocytic activity of microglia, hence modulating their tau‐directed activity. Method We utilized age‐ and sex‐matched Irf5 +/+ (WT) and Irf5 ⁻ / ⁻ littermate mice for the analysis of ex vivo phagocytic activity of primary microglia, at steady‐state and triggered by tau. We examined microglia morphology and numbers under these conditions and with ageing. Last, we injected PHF tau intracranially to WT and Irf5 ⁻ / ⁻ mice, monitoring tau accumulation and IRF5 response. Result 1) Irf5 ⁻ / ⁻ microglia have higher baseline phagocytic activity compared to WT microglia, which may be modulated by tau. 2) Microglia numbers are reduced in ageing Irf5 ⁻ / ⁻ 3) PHF tau‐injected Irf5 ⁻ / ⁻ mice show significant soluble tau accumulation, but a different pattern of oligomeric and insoluble tau accumulation with age. 4) In WT mice, the PHF tau‐injected hemisphere showed significantly higher levels of IRF5 compared to the contralateral, confirming a specific response of IRF5 to tau. Conclusion Tau is a specific activator of microglia and of the IRF5 pathway, which can modulate microglia response to pathology. Ageing is an active variable in the process, affecting the pattern of microglia response to tau, differentially in WT and Irf5 ⁻ / ⁻ mice . Modulating the IRF5 pathway may be a viable therapeutic approach in tauopathies.

The transcription factor NRF2 plays a crucial role in the regulation of antioxidant cell responses to stressors. It controls a plethora of genes with pro-surviving activity, among which heme oxygenase 1 (HO-1) has been recognized to play a potent anti-inflammatory activity through its metabolites carbon monoxide (CO) and bilirubin. Macrophages trigger inflammation by recognizing pathogens and tissue damage using different toll like receptors (TLRs) that through the activation of complex signalling pathways lead to specific cell responses. In particular, TLR4 and TLR7/8 have been proved to have downstream signal cascades highly interrelated, involving both NF-kB and interferon regulatory factor 5 (IRF5) transcription factors and leading to pro-inflammatory cytokine release (e.g. TNF-α). Interestingly, IRF5 has been proved to be dysregulated in autoimmune diseases, cancer, cardiovascular diseases and neuroinflammation. Thus, our work aims at understanding the involvement of NRF2/HO-1 in the regulation of IRF5, which has never been investigated.

Background: Cardiac arrest (CA) can lead to neuronal degeneration and death through various pathways, including oxidative, inflammatory, and metabolic stress. However, current neuroprotective drug therapies will typically target only one of these pathways, and most single drug attempts to correct the multiple dysregulated metabolic pathways elicited following cardiac arrest have failed to demonstrate clear benefit. Many scientists have opined on the need for novel, multidimensional approaches to the multiple metabolic disturbances after cardiac arrest. In the current study, we have developed a therapeutic cocktail that includes ten drugs capable of targeting multiple pathways of ischemia–reperfusion injury after CA. We then evaluated its effectiveness in improving neurologically favorable survival through a randomized, blind, and placebo-controlled study in rats subjected to 12 min of asphyxial CA, a severe injury model. Results: 14 rats were given the cocktail and 14 received the vehicle after resuscitation. At 72 h post-resuscitation, the survival rate was 78.6% among cocktail-treated rats, which was significantly higher than the 28.6% survival rate among vehicle-treated rats (log-rank test; p = 0.006). Moreover, in cocktail-treated rats, neurological deficit scores were also improved. These survival and neurological function data suggest that our multi-drug cocktail may be a potential post-CA therapy that deserves clinical translation. Conclusions: Our findings demonstrate that, with its ability to target multiple damaging pathways, a multi-drug therapeutic cocktail offers promise both as a conceptual advance and as a specific multi-drug formulation capable of combatting neuronal degeneration and death following cardiac arrest. Clinical implementation of this therapy may improve neurologically favorable survival rates and neurological deficits in patients suffering from cardiac arrest.

About 2% of Alzheimer's disease (AD) cases have early onset (FAD) and are caused by mutations in either Presenilins (PSEN1/2) or Amyloid-β Precursor Protein (APP). PSEN1/2 catalyze production of Aβ peptides of different length from APP. Aβ peptides are the major components of amyloid plaques, a pathological lesion that characterizes AD. Analysis of mechanisms by which PSEN1/2 and APP mutations affect Aβ peptide compositions lead to the implication of the absolute or relative increase in Aβ42 in amyloid-β plaques formation. Here, to elucidate the formation of pathogenic Aβ cocktails leading to amyloid pathology, we utilized FAD rat knock-in models carrying the Swedish APP (Apps allele) and the PSEN1 L435F (Psen1LF allele) mutations. To accommodate the differences in pathogenicity of rodent and human Aβ, these rat models are genetically engineered to express human Aβ species as both the Swedish mutant allele and the wild-type rat allele (called Apph) have been humanized in the Aβ-coding region. Analysis of the 8 possible FAD mutant permutations indicates that the CNS levels of Aβ43, rather than absolute or relative increases in Aβ42, determine the onset of pathological amyloid deposition in FAD knock-in rats. Notably, Aβ43 was found in amyloid plaques in late onset AD (LOAD) and Mild Cognitive impairment (MCI) cases, suggesting that the mechanisms initiating amyloid pathology in FAD knock-in rat reflect disease mechanisms driving amyloid pathology in LOAD. This study helps clarifying the molecular determinants initiating amyloid pathology, and supports therapeutic interventions targeting Aβ43 in AD.