Alzheimer’s disease (AD) is the most common cause of dementia and affects a large portion of the elderly population worldwide. Currently, a diagnosis of AD depends on the clinical symptoms of dementia, magnetic resonance imaging to determine brain volume, and positron emission tomography imaging to detect brain amyloid or tau deposition. The best characterized biological fluid markers for AD are decreased levels of amyloid β-protein (Aβ) 42 and increased levels of phosphorylated tau and total tau in cerebrospinal fluid (CSF). However, less invasive and easily detectable biomarkers for the diagnosis of AD, especially at the early stage, are still under development. Here, we provide an overview of various biomarkers identified in CSF and blood for the diagnostics of AD over the last 25 years. CSF biomarkers that reflect the three hallmarks of AD, amyloid deposition, neurofibrillary tangles, and neurodegeneration, are well established. Based on the need to start treatment in asymptomatic people with AD and to screen for AD risk in large numbers of young, healthy individuals, the development of biomarkers for AD is shifting from CSF to blood. Elements of the core pathogenesis of AD in blood, including Aβ42, tau proteins, plasma proteins, or lipids have shown their usefulness and capabilities in AD diagnosis. We also highlight some novel identified blood biomarkers (including Aβ42/Aβ43, p-tau 181, Aβ42/APP669-711, structure of Aβ in blood, and flotillin) for AD.

Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic β-amyloid protein 42 (Aβ42) to Aβ40. Because of its neurotoxicity, Aβ42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aβ40 has neuroprotective effects against Aβ42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aβ42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40–converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE^+/− mice and found that a decrease in ACE levels promoted Aβ42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

Genetic diversity in the apolipoprotein E (ApoE) gene has been identified as the major susceptibility genetic risk factor for sporadic Alzheimer’s disease (SAD). Specifically, the ApoEε4 allele is a significant risk factor for SAD, while ApoEε2 allele provides protection compared to the more common ApoEε3 allele. This review discusses the role of the ApoE in AD and other neurodegenerative disorders. ApoE, a cholesterol transport protein, influences several pathways involved in neurodegeneration, particularly in AD. Beyond its established role in amyloid β-protein (Aβ) metabolism and deposition, ApoE also impacts tau pathology, neurodegeneration, and the microglial response to AD. The review aims to provide an updated overview of ApoE’s diverse roles, emphasizing its involvement in Aβ clearance through ApoE receptors. It also covers ApoE’s influence in other neurodegenerative diseases like Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Huntington’s disease (HD), vascular dementia (VD), and multiple sclerosis (MS). New research highlights the interaction between ApoE and presenilin (PS), suggesting connections between familial AD (FAD) and SAD. The review also explores protective effects of ApoE mutations against AD and ApoE4-induced tauopathy, neurodegeneration, and neuroinflammation. The insights from this comprehensive update could indeed lead to new therapeutic strategies for neurodegenerative diseases.

Presenilin, a transmembrane protein primarily known for its role in Alzheimer’s disease (AD) as part of the γ-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic role. This review aims to provide a comprehensive overview of presenilin’s diverse roles in AD and other neurodegenerative disorders. It includes a summary of well-known substrates of presenilin, such as its involvement in amyloid precursor protein (APP) processing and Notch signaling, along with other functions. Additionally, it highlights newly discovered functions, such as trafficking function, regulation of ferritin expression, apolipoprotein E (ApoE) secretion, the interaction of ApoE and presenilin, and the Aβ42-to-Aβ40-converting activity of ACE. This updated perspective underscores the evolving landscape of presenilin research, emphasizing its broader impact beyond established pathways. The incorporation of these novel findings accentuates the dynamic nature of presenilin’s involvement in cellular processes, further advancing our comprehension of its multifaceted roles in neurodegenerative disorders. By synthesizing evidence from a range of studies, this review sheds light on the intricate web of presenilin functions and their implications in health and disease.

Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of β-amyloid-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25–40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39 °C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF) and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx-defective-1 (APH-1), and nicastrin (NCT) but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30 °C) compared with those housed at standard room temperature (23 °C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.

Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β (Aβ) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENTFamilial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-β 42 (Aβ42)/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aβ clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretionin vitroand in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.