Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum

Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer’s disease (AD), and like AD, it is highly influenced by genetics with heritability estimates of 32–63%. We thus hypothesized that genetics underlying peripheral blood total cholesterol (TC) levels could influence the risk of developing AD. We created a weighted polygenic score (TC-PGS) using summary data from a meta-analysis of TC genome-wide association studies for evaluation in three independent AD-related cohorts spanning pre-clinical, clinical, and pathophysiologically proved AD. APOE-ε4 variant was purposely included in the analysis as it represents an already well-established genetic risk factor for both AD and circulating TC. We could vastly improve the performance of the score when considering p-value thresholds for inclusion in the score, sex, and statin use. This optimized score (p-value threshold of 1 × 10−6 for inclusion in the score) explained 18.2% of the variance in TC levels in statin free females compared to 6.9% in the entire sample and improved prediction of hypercholesterolemia (receiver operator characteristics analysis revealed area under the curve increase from 70.8% to 80.5%). The TC-PGS was further evaluated for association with AD risk and pathology. We found no association between the TC-PGS and either of the AD hallmark pathologies, assessed by cerebrospinal fluid levels of Aβ-42, p-Tau, and t-Tau, and 18F-NAV4694 and 18F-AV-1451 positron emission tomography. Similarly, we found no association with the risk of developing amyloid pathology or becoming cognitively impaired in individuals with amyloid pathology.

ACE2/ANG-(1-7)/Mas Receptor Axis Activation Prevents Inflammation, Glial Activation And Cognitive Decline In a Rat Model of STZ Induced Impairment of Learning and Memory

Activation of the renin-angiotensin system (RAS), mediated by Angiotensin converting enzyme/Angiotensin II/Angiotensin receptor-1 (ACE/Ang II/AT1 R) axis elicits amyloid pathology, induces neurodegeneration and cognitive impairment leading to Alzheimer's disease (AD). On the contrary, Angiotensin converting enzyme2 (ACE2) produces Ang -(1-7) which binds with the Mas receptor and counters ACE/Ang II/AT1 axis. To date, the involvement of ACE2/Ang-(1–7)/MasR axis in etiology and progression of AD largely remains to be elucidated. Hence, the present study is aimed to determine the role of ACE2/Ang-(1–7)/MasR axis in STZ induced model of neurodegeneration using Diminazene aceturate (DIZE), an ACE2 activator in both in vitro/in vivo experimental conditions. Interestingly, ROS content and oxidative stress burden in N2A cells were found to be attenuated along with a decrease in enzymatic activity of AChE following DIZE treatment. In contrast, activation of this axis led to altered mitochondrial membrane potential (MMP) in addition to ablated intracellular Ca2+ influx. ACE2/Ang-(1–7)/MasR axis activation further resulted in reduction of astrogliosis as indicated by decreased intensity of NFκB and dwindled expression of its downstream NLRP3 cascade signaling molecules. These results were confirmed by using a selective inhibitor of ACE-2, MLN-4760, which reversed the protective effects of ACE2 activation by DIZE. Subsequently, treatment with DIZE in STZ induced rat model of AD prevented cognitive impairment and progression of amyloid pathology. Therefore, the involvement of ACE2/Ang-(1–7)/Mas axis suggests that it could be further explored as a potential pathway in AD, owing to its inhibitory effect on inflammation/astrogliosis and restoring cognitive functions.

Hippocampal disruptions of synaptic and astrocyte metabolism are primary events of early amyloid pathology in the 5xFAD mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, this crucial metabolic interplay during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in the 5xFAD hippocampus. This hyperactive neuronal phenotype coincided with decreased hippocampal tricarboxylic acid (TCA) cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity and decreased glutamine synthesis led to hampered neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, the cerebral cortex of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism, which may suggest a metabolic compensation in this brain region. We found limited changes when we explored the brain proteome and metabolome of the 5xFAD mice, supporting that the functional metabolic disturbances between neurons and astrocytes are early primary events in AD pathology. In addition, synaptic mitochondrial and glycolytic function was selectively impaired in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex regional and cell-specific metabolic adaptations in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunctions in AD.