抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence.

Ageing as a risk factor for neurodegenerative disease.

Several attempts have been made to treat Alzheimer's disease (AD) using anti-amyloid strategies with disappointing results It is clear that the "amyloid cascade hypothesis" alone cannot fully explain the neuronal damage in AD, as evidenced both by autopsy and imaging studies Neuroinflammation plays a significant role in neurodegenerative diseases, whereas the debate is ongoing about its precise role, whether it is protective or harmful In this review, we focus on the potential mechanism of glial activation and how local and systemic factors influence disease progression We focus on neuroinflammation in AD, especially in the earliest stages, a vicious cycle of glial priming, release of pro-inflammatory factors, and neuronal damage We review the evidence from imaging studies, regarding the temporal relationship between amyloid deposition and neuroinflammation, the influence of systemic inflammation on glial activation, both in acute and chronic stimulation and the relevance of inflammation as a diagnostic and therapeutic target

Neuroinflammation in Alzheimer's disease: Current evidence and future directions

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

One of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders is achieving sufficient blood-brain barrier (BBB) penetration. Research in the past few decades has revealed that the BBB is not only a substantial barrier for drug delivery to the CNS but also a complex, dynamic interface that adapts to the needs of the CNS, responds to physiological changes, and is affected by and can even promote disease. This complexity confounds simple strategies for drug delivery to the CNS, but provides a wealth of opportunities and approaches for drug development. Here, I review some of the most important areas that have recently redefined the BBB and discuss how they can be applied to the development of CNS therapeutics.

From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery

While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE e4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE e4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

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Krista R. Kawaguchi

Papers

Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline