Is Alzheimer’s Disease a Liver Disease of the Brain?

Abstract

Clinical specialization is not only a force for progress, but it has also led to the fragmentation of medical knowledge. The focus of research in the field of Alzheimer's disease (AD) is neurobiology, while hepatologists focus on liver diseases and lipid specialists on atherosclerosis. This article on AD focuses on the role of the liver and lipid homeostasis in the development of AD. Amyloid-␤ (A␤) deposits accumulate as plaques in the brain of an AD patient long before cognitive decline is evident. A␤ generation is a normal physiological process; the steady-state level of A␤ in the brain is determined by balance between A␤ production and its clearance. We present evidence suggesting that the liver is the origin of brain A␤ deposits and that it is involved in peripheral clearance of circulating A␤ in the blood. Hence the liver could be targeted to decrease A␤ production or increase peripheral clearance.

Retinal Thickness Changes Over Time in a Murine AD Model APPNL-F/NL-F

“…In the APP NL−F/NL−F mice, the time between 9 and 15 months of age was characterized by a slow and progressive tendency toward thickening of the retina with alternation of thinned retinal sectors, which vary over time and present only statistical significance at 15 months in some sectors of the total retinal thickness (outer and inner rings of inferior sector and inner ring of the temporal sector). These changes could correlate to the brain changes seen in this model at 9 months, when neuronal death was detected by necrosis in the cerebral cortex (Schedin-Weiss et al, 2020 ). At the same time, the effect of microgliosis and astrogliosis are significant in the APP NL−F/NL−F model in the cortex, hippocampus, and subcortical region compared to the WT mice (Masuda et al, 2016 ).…”

“…In addition, the accumulation of Aβ is age-dependent from 1 to 18 months (Petrache et al, 2019 ). Aβ brain deposits have been reported at 6 months of age in this AD model (Saito et al, 2014 ), developing first in the hippocampus and then becoming more significant in the cerebral cortex (Schedin-Weiss et al, 2020 ). At 9 months old, there was a significant amount of Aβ plaques in the parenchymal brain, with the Aβ plaque load reaching its maximum at 18 months (Schedin-Weiss et al, 2020 ).…”

“…In APP NL−F/NL−F model, at 3 months old, there was no presence of Aβ pathology, although there was already an alteration of the proteome in both the hippocampus and the cortex compared to WT mice. The early increase in Tris-soluble Aβ 42 levels suggests that the pre-symptomatic stages of AD begin before amyloidosis Aβ (Schedin-Weiss et al, 2020 ). In addition, the accumulation of Aβ is age-dependent from 1 to 18 months (Petrache et al, 2019 ).…”

“…The findings at this early time may also be secondary to the astrocyte reduction of glutamate synaptic recapture (Li et al, 2009 ) and to the excessive amount of Aβ dimers, as well as the Aβ 1−40 monomers and dimers, which increase the presynaptic release of glutamate (Fogel et al, 2014 ). Therefore, a combination of both causes could increase residual glutamate levels, thereby promoting neuronal hyperactivity, which is a precursor to plaque formation (Busche and Konnerth, 2016 ; Schedin-Weiss et al, 2020 ).…”

Circulating insulin-like growth factor I is involved in the effect of diet on peripheral amyloid β clearance

“…Thus, increased peripheral Aβ levels after anti-Aβ treatment was reported to parallel a decrease of brain Aβ; reducing peripheral Aβ was su cient to reduced brain Aβ, and recent studies favor a diagnostic utility of the relationship between plasma and CSF Aβ 1 − 42 [35,48,49]. Thus, the relationship between peripheral and central Aβ is still under debate [50]; indeed, a substantial part of brain Aβ clearance in humans takes place in the periphery [51].…”