The existence of individuals who remain cognitively intact despite presenting histopathological signs of Alzheimer's disease (AD), here referred to as “Nondemented with AD neuropathology” (NDAN), suggests that some mechanisms are triggered to resist cognitive impairment. Exposed phosphatidylserine (ePS) represents a neuronal “eat‐me” signal involved in microglial‐mediated phagocytosis of damaged synapses. A possible mediator of this process is TREM2, a microglial surface receptor activated by ligands including PS. Based on TREM2 role in the scavenging function of microglia, we hypothesize that an efficient microglial phagocytosis of damaged synapses underlies synaptic resilience in NDAN, thus protecting from memory deficits. Using immunofluorescence microscopy, we performed a comparative study of human post‐mortem frontal cortices of aged‐matched, AD and NDAN individuals. We studied the distribution of activated microglia (IBA1, IBA1+/CD68+ cells) and phagocytic microglia‐related proteins (TREM2, DAP12), demonstrating higher microglial activation and TREM2 expression in NDAN versus AD. A study of the preservation of synapses around plaques, assessed using MAP2 and βIII tubulin as dendritic and axonal markers, respectively, and PSD95 as a postsynaptic marker, revealed preserved axonal/dendritic structure around plaques in NDAN versus AD. Moreover, high levels of PSD95 around NDAN plaques and the colocalization of PSD95 with CD68 indicated a prompt removal of damaged synapses by phagocytic microglia. Furthermore, Annexin V assay on aged‐matched, AD and NDAN individuals synaptosomes revealed increased levels of ePS in NDAN, confirming damaged synapses engulfment. Our results suggest a higher efficiency of TREM2‐induced phagocytic microglia in removing damaged synapses, underlying synaptic resilience in NDAN individuals.

TREM2‐induced activation of microglia contributes to synaptic integrity in cognitively intact aged individuals with Alzheimer's neuropathology

Alzheimer’s disease is the most common form of neurodegenerative disease, and increasing evidence shows that insulin signaling has crucial roles in AD initiation and progression. In this study, we explored the effect and underlying mechanism of SQW, a representative formula for tonifying the kidney and promoting yang, on improving the cognitive function in a streptozotocin-induced model of AD rats. We investigated memory impairment in the AD rats by using the Morris water test. HE and Nissl staining were employed to observe the histomorphological changes in the hippocampal. Expression levels of NeuN and proteins related to Tau and apoptosis were measured using immunohistochemistry and Western blotting, respectively. Additionally, we performed RNA sequencing, and the selected hub genes were then validated by qRT-PCR. Furthermore, the protein expression levels of PI3K/AKT pathway-related proteins were detected by Western blot. We found that SQW treatment significantly alleviated learning and memory impairment, pathological damage, and apoptosis in rats, as evidenced by an increased level of NeuN and Bcl-2, and decreased phosphorylation of Tau, Bax, and Caspase-3 protein expression. SQW treatment reversed the expression of insulin resistance-related genes (Nr4a1, Lpar1, Bdnf, Atf2, and Ppp2r2b) and reduced the inhibition of the PI3K/AKT pathway. Our results demonstrate that SQW could contribute to neuroprotection against learning and memory impairment in rats induced by STZ through activation of the PI3K/AKT pathway.

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Shen Qi Wan Ameliorates Learning and Memory Impairment Induced by STZ in AD Rats through PI3K/AKT Pathway

Neuropeptide S promotes maintenance of newly formed dendritic spines and performance improvement after motor learning in mice

Simple Summary The median age of diagnosis of dementia, as well as for many cancers, is above 60 years. Dementia should not exclude even frail, elderly patients from cancer treatment. Before beginning any treatment, the effects of the patient’s diet, medications and caregiver situation on neurological symptoms should be determined. Malnutrition, dehydration, alcohol consumption, and even loneliness can all accentuate or cause the “3Ds” of dementia, delirium and depression. Common drugs, especially if taken together, can cause cognitive difficulties resembling neurodegenerative diseases such as Alzheimer or Parkinson. These syndromes may be reversed by diet, social and caregiver changes, and stopping or lowering the dose of potentially inappropriate medications (PIMs). Brain scans and genetic analysis can be used to guide immunotherapies and tumor-antigen directed treatments. Discussion among the patient, caregivers and medical team is needed to assess cognition state and ability to accept diagnostic and therapeutic procedures. While surgery may be too dangerous for frail patients, radiation and many oral or infusion therapies, some discussed in this review, may be better tolerated. Abstract The likelihood of a diagnosis of dementia increases with a person’s age, as is also the case for many cancers, including melanoma and multiple myeloma, where the median age of diagnosis is above 60 years. However, patients diagnosed with dementia are less likely to be offered invasive curative therapies for cancer. Together with analysis of diet and medication history, advanced imaging methods and genetic profiling can now indicate more about syndromes causing the neurological symptoms. Cachexia, malnutrition, dehydration, alcohol consumption, and even loneliness can all accentuate or cause the “3Ds” of dementia, delirium and depression. Many common drugs, especially in the context of polypharmacy, can cause cognitive difficulties resembling neurodegenerative disease. These syndromes may be reversed by diet, social and caregiver changes, and stopping potentially inappropriate medications (PIMs). More insidious are immune reactions to many different autoantigens, some of which are related to cancers and tumors. These can induce movement and cognitive difficulties that mimic Alzheimer’s and Parkinson’s diseases and other ataxias associated with aging. Paraneoplastic neurological syndromes may be reversed by directed immunotherapies if detected in their early stages but are best treated by removal of the causative tumor. A full genetic workup should be done for all individuals as soon as possible after diagnosis, to guide less invasive treatments suitable for frail individuals. While surgical interventions may be contraindicated, genetic profile guided immunotherapies, oral treatments, and radiation may be equally curative in a significant number of cancers.

https://www.mdpi.com/2072-6694/15/4/1055/pdf?version=1676861685

Distinguishing Curable from Progressive Dementias for Defining Cancer Care Options

Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer's disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer's pathogenesis and progression. Aβ has been the prime target for the development of AD therapy. However, the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer's drug has followed the correct course. However, the recent successes of Aβ targeted trials have assuaged those doubts. In this review, we discussed the evolution of the amyloid cascade hypothesis over the last 30 years and summarized its application in Alzheimer's diagnosis and modification. In particular, we extensively discussed the pitfalls, promises and important unanswered questions regarding the current anti-Aβ therapy, as well as strategies for further study and development of more feasible Aβ-targeted approaches in the optimization of AD prevention and treatment. 

/pdf/amyloid-b-based-therapy-for-alzheimers-disease-challenges-28xmf2dn.pdf

Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

Alzheimer's disease (AD) is characterized by progressive cognitive decline due to accumulating synaptic insults by toxic oligomers of amyloid beta (AβO) and tau (TauO). There is growing consensus that preventing these oligomers from interacting with synapses might be an effective approach to treat AD. However, recent clinical trial failures suggest low effectiveness of targeting Aβ in late-stage AD. Researchers have redirected their attention toward TauO as the levels of this species increase later in disease pathogenesis. Here we show that AβO and TauO differentially target synapses and affect each other's binding dynamics.Binding of labeled, pre-formed Aβ and tau oligomers onto synaptosomes isolated from the hippocampus and frontal cortex of mouse and postmortem cognitively intact elderly human brains was evaluated using flow-cytometry and western blot analyses. Binding of labeled, pre-formed Aβ and tau oligomers onto mouse primary neurons was assessed using immunofluorescence assay. The synaptic dysfunction was measured by fluorescence analysis of single-synapse long-term potentiation (FASS-LTP) assay.We demonstrated that higher TauO concentrations effectively outcompete AβO and become the prevailing synaptic-associated species. Conversely, high concentrations of AβO facilitate synaptic TauO recruitment. Immunofluorescence analyses of mouse primary cortical neurons confirmed differential synaptic binding dynamics of AβO and TauO. Moreover, in vivo experiments using old 3xTgAD mice ICV injected with either AβO or TauO fully supported these findings. Consistent with these observations, FASS-LTP analyses demonstrated that TauO-induced suppression of chemical LTP was exacerbated by AβO. Finally, predigestion with proteinase K abolished the ability of TauO to compete off AβO without affecting the ability of high AβO levels to increase synaptic TauO recruitment. Thus, unlike AβO, TauO effects on synaptosomes are hampered by the absence of protein substrate in the membrane.These results introduce the concept that TauO become the main synaptotoxic species at late AD, thus supporting the hypothesis that TauO may be the most effective therapeutic target for clinically manifest AD. 

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Junbo Wang

Papers

Aβ/tau oligomer interplay at human synapses supports shifting therapeutic targets for Alzheimer’s disease