Metabolic Syndrome and the Cellular Phase of Alzheimer's Disease

Alzheimer's disease (AD) is characterized by cognitive dysfunction and progressive neurodegeneration. The major hallmarks of AD pathology are amyloid plaques and neurofibrillary tangles. However, AD often coexists with other brain microvascular lesions caused by comorbidities, including obesity, diabetes, hypertension, and cardiovascular diseases. The risk factors for these comorbidities are collectively referred to as metabolic syndrome (MetS). Clinical AD is preceded by decades of prodromal cellular phase. During this asymptomatic phase, systemic changes caused by MetS can play critical roles in driving neuroinflammation, an important cause of AD pathogenesis. Studies of MetS and AD have traditionally remained in distinct domains. The cross talk between MetS and the cellular phase of AD is an important area to be investigated. AD risk factors identified by genome-wide association studies (GWAS) have strongly suggested the role of microglia, the resident immune cells of the brain, in AD pathogenesis. Microglial dysregulation is caused not only by CNS-intrinsic factors but also by systemic changes. MetS appears to cause brain mitochondrial dysfunction through a defective NAD⁺-sirtuin pathway. Sirtuins are a family of seven proteins that are involved in longevity and inflammation. Among them, SIRT3 is exclusively present in mitochondria, playing a significant role in metabolic adaptation. SIRT3 deacetylates and activates key metabolic enzymes and transcriptional regulators, utilizing NAD⁺ in the process. MetS could prime microglia through the interface of blood-brain barrier (BBB). Age-dependent breakdown of the BBB has been reported in human subjects. The neurovascular unit at BBB consists of brain microvascular endothelial cells, end feet of astrocytes, and pericytes. Therapeutic targeting of the sirtuin pathway in AD with coexisting pathologies has the potential to produce profoundly beneficial effects in improving mitochondrial function and decreasing neuroinflammation.