Amino Acid Catabolism in Alzheimer’s Disease Brain: Friend or Foe?

Abstract

There is a dire need to discover new targets for Alzheimer's disease (AD) drug development. Decreased neuronal glucose metabolism that occurs in AD brain could play a central role in disease progression. Little is known about the compensatory neuronal changes that occur to attempt to maintain energy homeostasis. In this review using the PubMed literature database, we summarize evidence that amino acid oxidation can temporarily compensate for the decreased glucose metabolism, but eventually altered amino acid and amino acid catabolite levels likely lead to toxicities contributing to AD progression. Because amino acids are involved in so many cellular metabolic and signaling pathways, the effects of altered amino acid metabolism in AD brain are far-reaching. Possible pathological results from changes in the levels of several important amino acids are discussed. Urea cycle function may be induced in endothelial cells of AD patient brains, possibly to remove excess ammonia produced from increased amino acid catabolism. Studying AD from a metabolic perspective provides new insights into AD pathogenesis and may lead to the discovery of dietary metabolite supplements that can partially compensate for alterations of enzymatic function to delay AD or alleviate some of the suffering caused by the disease.

Novel Blood Biomarkers that Correlate with Cognitive Performance and Hippocampal Volumetry: Potential for Early Diagnosis of Alzheimer’s Disease

“…Levels of BCAAs were tested because excess or limiting dietary BCAA causes neurological dysfunction, reducing cognitive function, however, the mechanisms underlying these links are not entirely understood and require further investigation. Several studies have reported the amino acid profiles in the CSF and plasma of individuals with MCI and AD, generating a mixed data set with wide variability possibly due to study design, methodologies or instrumentation [55]. We show here that levels of leucine, isoleucine and valine independently and together are lower in Control relative to MCI and AD participants.…”

Red blood cell metabolism in Down syndrome: hints on metabolic derangements in aging

“…28,29 Although merely speculative at this stage, it is fascinating to highlight the observed decreases in methionine levels of T21 RBCs and previous reports on the role of this metabolite in cognitive impairment, such as AD. 30 Of note, in D21 individuals, excess plasma methionine or methionine supplementation are noted to promote the onset of AD, 30,31 an observation that may not hold true in T21 subjects. Because cystathionine-b-synthase is coded by a gene on chromosome 21, 32 increased expression of this enzyme impacts homocysteine metabolism by impairing folate-dependent methionine resynthesis and availability of active folate (folate trap), 32 an etiological factor of macrocytosis and shorter survival of RBCs, 15 the richest cell by iron content in the human body.…”

Metabolomic‐guided discovery of Alzheimer's disease biomarkers from body fluid

“…Glucose hypometabolism has been repeatedly reported to occur in AD brain, and this could play a central role in disease progression. Amino acid oxidation can temporarily compensate for the decreased glucose metabolism, but eventually altered amino acid and amino acid catabolite levels likely lead to toxicities contributing to AD progression (Griffin and Bradshaw, ). Kori et al () also found a similar pattern and proposed that alanine, aspartate, glutamate, and purine metabolism might act as alternative pathways to overcome inadequate glucose supply and energy crisis in neurodegeneration.…”