Hallmarks of aging: An expanding universe

The biological processes that are disrupted in the Alzheimer's disease (AD) brain remain incompletely understood. In this study, we analyzed the proteomes of more than 1,000 brain tissues to reveal new AD-related protein co-expression modules that were highly preserved across cohorts and brain regions. Nearly half of the protein co-expression modules, including modules significantly altered in AD, were not observed in RNA networks from the same cohorts and brain regions, highlighting the proteopathic nature of AD. Two such AD-associated modules unique to the proteomic network included a module related to MAPK signaling and metabolism and a module related to the matrisome. The matrisome module was influenced by the APOE ε4 allele but was not related to the rate of cognitive decline after adjustment for neuropathology. By contrast, the MAPK/metabolism module was strongly associated with the rate of cognitive decline. Disease-associated modules unique to the proteome are sources of promising therapeutic targets and biomarkers for AD. 

/pdf/large-scale-deep-multi-layer-analysis-of-alzheimers-disease-2ibj948w.pdf

Large-scale deep multi-layer analysis of Alzheimer’s disease brain reveals strong proteomic disease-related changes not observed at the RNA level

2-Deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) is widely used to study cerebral glucose metabolism. Here, we investigated whether the FDG-PET signal is directly influenced b...

Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases.

Ageing leads to profound alterations in the immune system and increases susceptibility to some chronic, infectious and autoimmune diseases. In recent years, widespread application of single-cell techniques has enabled substantial progress in our understanding of the ageing immune system. These comprehensive approaches have expanded and detailed the current views of ageing and immunity. Here we review a body of recent studies that explored how the immune system ages using unbiased profiling techniques at single-cell resolution. Specifically, we discuss an emergent understanding of age-related alterations in innate and adaptive immune cell populations, antigen receptor repertoires and immune cell-supporting microenvironments of the peripheral tissues. Focusing on the results obtained in mice and humans, we describe the multidimensional data that align with established concepts of immune ageing as well as novel insights emerging from these studies. We further discuss outstanding questions in the field and highlight techniques that will advance our understanding of immune ageing in the future.

Immune ageing at single-cell resolution.

Cellular senescence at the crossroads of inflammation and Alzheimer's disease

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.

Restoring metabolism of myeloid cells reverses cognitive decline in ageing

Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine As-related pathology in “preclinical AD.” Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in AppNL-G-F mice compared to AppNL animals which served as controls. We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of AppNL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function.

/pdf/the-two-faces-of-synaptic-failure-in-app-nl-g-f-knock-in-2481bwzp7t.pdf

The two faces of synaptic failure in App NL-G-F knock-in mice

/pdf/commentary-app-as-a-mediator-of-the-synapse-pathology-in-4n8oi21hck.pdf

Commentary: APP as a Mediator of the Synapse Pathology in Alzheimer's Disease.

In tauopathy mouse models, activity‐dependent synaptic plasticity, as measured by long‐term potentiation (LTP), is compromised. Treatment of tauopathy mice with LM11A‐31, a small molecule modulator of p75 neurotrophin receptor signaling, normalizes LTP. In the present study, we determined whether activity‐dependent gene expression profiles would be altered in stimulated hippocampus (HC) of tauopathy mice, and if prior in vivo treatment with LM11A‐31 would normalize elements of their transcriptional signature.

https://alz-journals.onlinelibrary.wiley.com/doi/pdf/10.1002/alz.045764

Amira Latif-Hernandez

Papers

Restoring metabolism of myeloid cells reverses cognitive decline in ageing

The two faces of synaptic failure in App NL-G-F knock-in mice

Commentary: APP as a Mediator of the Synapse Pathology in Alzheimer's Disease.

Elucidating emerging therapeutics: P75 receptor modulation reverts tauopathy associated alterations in synapse-relevant gene expression signatures