Why do anti-amyloid beta antibodies not work? Time to reconceptualize dementia pathophysiology by incorporating astrocyte melatonergic pathway desynchronization from amyloid-beta production

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

“…The induction of both NAS and melatonin is dependent upon optimized mitochondrial function and the conversion of pyruvate to acetyl-CoA, indicating that one of the problems of suboptimal mitochondrial function is the suppressed capacity to upregulate the melatonergic pathway. This clearly requires investigation, given the protection afforded by melatonin against the oligomerization and damage caused by amylin in pancreatic β-cells, and may parallel recent work indicating the role of suppressed astrocyte melatonergic pathway in the accumulation of amyloid-β in dementia [ 97 ]. Beta-site amyloid precursor protein cleaving enzyme (BACE1) is also highly expressed in pancreatic β-cells where it acts to regulate insulin mRNA expression levels [ 136 ], whilst the inhibition of BACE2 increases pancreatic β-cell function and insulin production [ 137 ].…”

“…A plethora of studies have highlighted the role of pancreatic β-cell mitochondria as a crucial aspect of T1DM pathophysiology. Recent work indicates that the mitochondrial melatonergic pathway may be a core aspect of mitochondrial function, with relevance across a host of diverse medical conditions, including Alzheimer’s disease [ 97 , 98 ], multiple sclerosis [ 99 , 100 ], glioblastoma [ 101 , 102 ], breast cancer [ 103 , 104 ], depression [ 105 , 106 ], and amyotrophic lateral sclerosis [ 7 , 107 , 108 ]. Integrating the melatonergic pathway into the biological underpinnings of T1DM allows for the inclusion of previous disparate bodies of data, providing a conceptualization of T1DM that has treatment and future research implications.…”

“…The tryptophan–melatonin pathway is evident in cells across body organs and tissues, with relevance to a host of diverse medical conditions, including depression [ 36 ], amyotrophic lateral sclerosis [ 7 ], cancers [ 113 ] and dementia [ 97 ]; see Figure 1 . Most tryptophan is derived from dietary sources, although the shikimate pathway in the human gut microbiome is a relevant provider of aromatic amino acids, including tryptophan, as well as tyrosine and phenylalanine [ 7 ].…”

“…Beta-site amyloid precursor protein cleaving enzyme (BACE1) is also highly expressed in pancreatic β-cells where it acts to regulate insulin mRNA expression levels [ 136 ], whilst the inhibition of BACE2 increases pancreatic β-cell function and insulin production [ 137 ]. The interactions of the melatonergic pathway with BACE1 and BACE2 regulation and effects in pancreatic β-cells will be important to determine and would seem likely to parallel melatonin’s protection against amyloid-β production in the CNS [ 97 ].…”

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

“…The interface of 'atomistic' and 'holistic' data has always posed problems for medical classification and derived treatment, where a preference for simple biomarkers for a given cell or tissue is preferred due to its provision of a ready treatment target. This has proved problematic for more complex conditions, such as Alzheimer's disease, where the dogged persistence in pathophysiologically defining Alzheimer's disease by increased amyloid-β plaques and hyperphosphorylated tau-linked tangles for over 40 years has led to very little treatment improvement [13]. Recent data on other poorly conceptualized conditions, amyotrophic lateral sclerosis (ALS) and type 1 diabetes (T1DM), indicate that targeting the gut microbiome can slow/stop progression [14][15][16][17].…”