Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP‐CTFs in Alzheimer’s Disease

Abstract

Vascular dysfunctions, hypometabolism, and insulin resistance are high and early risk factors for Alzheimer's disease (AD), a leading neurological disease associated with memory decline and cognitive dysfunctions. Early defects in glucose transporters and glycolysis occur during the course of AD progression. Hypometabolism begins well before the onset of early AD symptoms; this timing implicates the vulnerability of hypometabolic brain regions to beta-secretase 1 (BACE-1) upregulation, oxidative stress, inflammation, synaptic failure, and cell death. Despite the fact that ketone bodies, astrocyte-neuron lactate shuttle, pentose phosphate pathway (PPP), and glycogenolysis compensate to provide energy to the starving AD brain, a considerable energy crisis still persists and increases during disease progression. Studies that track brain energy metabolism in humans, animal models of AD, and in vitro studies reveal striking upregulation of beta-amyloid precursor protein (β-APP) and carboxy-terminal fragments (CTFs). Currently, the precise role of CTFs is unclear, but evidence supports increased endosomal-lysosomal trafficking of β-APP and CTFs through autophagy through a vague mechanism. While intracellular accumulation of Aβ is attributed as both the cause and consequence of a defective endolysosomal-autophagic system, much remains to be explored about the other β-APP cleavage products. Many recent works report altered amino acid catabolism and expression of several urea cycle enzymes in AD brains, but the precise cause for this dysregulation is not fully explained. In this paper, we try to connect the role of CTFs in the energy translation process in AD brain based on recent findings.

Amyloid protein aggregates: new clients for mitochondrial energy production in the brain?

“…This finding supports the role of mitochondrial gamma-secretase activity in amyloid precursor protein (APP) cleavage and accumulation of proteolytic cleaved products within mitochondria-associated membranes (MAMs) [14]. While the accumulation of amyloidogenic products within mitochondria is believed to trigger a cascade of damaging processes, recent evidence suggests that cleaved amyloid proteins within the mitochondria may play some sort of protective role [15][16][17][18][19].…”

“…Taken together, there is evidence to support the role of protein aggregates in ATP turnover via the TCA cycle. In fact, the occurrence of brain–urea cycle activation in degenerative AD and HD is well indicated in several seminal works that are reviewed extensively and explained in detail in Fig. .…”

“…Several research groups have offered potential explanations. The hypothesis that endolysosomal proteolytic cleavage products of amyloid precursor protein carboxy-terminal fragments (APP-CTFs) can fuel hypometabolic AD brain through the mitochondrial TCA cycle [19,68] was validated by Li et al [40], who proposed that energy-related functions can be supported via toxic protein aggregates that accumulate in mitochondria [34]. Others suggest that mitochondria-mediated Ab clearance promotes learning and memory by reducing Ab levels and inflammation at synapses [69,70].…”

How Can Insulin Resistance Cause Alzheimer’s Disease?

“…In a hypometabolic state, amyloidosis increases based on the findings in animal studies and in vitro experiments [ 296 ]. Low glucose metabolism and insulin resistance in the brain stimulated BACE1 and GSK-3 activity [ 297 , 298 ].…”

Systemic Actions of SGLT2 Inhibition on Chronic mTOR Activation as a Shared Pathogenic Mechanism between Alzheimer’s Disease and Diabetes

“…Overwhelming results suggest that there are early abnormalities in cerebral glucose metabolism in people with AD [41,42], involving deficiencies in glycolysis and glucose transporters [43,44]. A candidate for a shared pathogenic mechanism linking these metabolically-driven conditions is represented by a chronic mechanistic target of rapamycin (mTOR) signaling activation [45].…”