Brain cells derived from Alzheimer’s disease patients have multiple specific innate abnormalities in energy metabolism

Abstract

Altered energy metabolism has been implicated both in aging and the pathogenesis of late-onset Alzheimer’s disease (LOAD). However, it is unclear which anomalies are acquired phenotypes and which are inherent and predispose to disease. We report that neural progenitor cells and astrocytes differentiated from LOAD patient-derived induced pluripotent stem cells exhibit multiple inter-related bioenergetic alterations including: changes in energy production by mitochondrial respiration versus glycolysis, as a consequence of alterations in bioenergetic substrate processing and transfer of reducing agents, reduced levels of NAD/NADH, diminished glucose uptake and response rates to insulin (INS)/IGF-1 signaling, decreased INS receptor and glucose transporter 1 densities, and changes in the metabolic transcriptome. Our data confirm that LOAD is a “multi-hit” disorder and provide evidence for innate inefficient cellular energy management in LOAD that likely predisposes to neurodegenerative disease with age. These processes may guide the development and testing of diagnostic procedures or therapeutic agents.

Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in iPSC-Derived Astrocytes in Alzheimer's Disease

“…Since glutamine is derived from the TCA cycle intermediate α-ketoglutarate via glutamate, astrocyte TCA cycle function is crucial for glutamine synthesis (Swanson and Graham, 1994). Multiple studies have revealed impaired astrocytic energy metabolism in AD (Oksanen et al, 2017;Dematteis et al, 2020;Andersen et al, 2021a;Ryu et al, 2021). It could, therefore, be speculated that the reduced synthesis of glutamate from oxidative leucine metabolism observed in the AD astrocytes may be caused by deficient astrocyte TCA cycle function, which may further hamper glutamine synthesis in AD.…”

Hydrogen Ion Dynamics as the Fundamental Link Between Neurodegenerative Diseases and Cancer. Its Application to the Therapeutics of Neurodegenerative Diseases with Special Emphasis in Multiple Sclerosis

“…A low pHi and pHe rapidly decreases neuronal transmission and activity, preceding the onset of neural cell death by apoptosis [17][18][19][20][21], the same as ASIC1 does [22]. In the same vein, accumulation of β-amyloid (βA) is directly induced by acidosis [11][12][13][14][16][17][18][19][20][21][22]104,106,107] (Figure 2 and Box 1). Further, low neural cell pHs induce protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation, which are hallmarks of Parkinson's disease (PD) [23].…”

“…Intracellular acidification is more pronounced in the brain of AD patients [11,107], while ßA aggregation in a mice model of AD is induced by acidosis and reverted upon microenvironmental alkalization, just as happens when using plasma rich in growth factors (PRGF) [16,21,[24][25][26]. Lowering pHi of neurons from 7.36 to 7.09/7.00 through exposure to nitric oxide (NO) sets in motion a programmed cell death program, increasing DNA fragmentation and decreasing cell survival ("low pHi-mediated metabolic collapse") [7,8,11,[27][28][29].…”

l-Lactate: Food for Thoughts, Memory and Behavior

“…Ryu and collaborators compared neural progenitor cells and astrocytes differentiated from late-onset AD patients. The authors found a significant downregulation of lactate dehydrogenase A in both cell types and that astrocytes from late-onset AD have a reduced metabolism of lactate [97].…”