White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Abstract

We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer’s disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer’s initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer’s disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.

Neuronal tau pathology worsens late-phase white matter degeneration after traumatic brain injury in transgenic mice

“…Demyelination can lead to further neurodegeneration since myelination protects vulnerable denuded axons and provides bioenergetic and trophic support [ 50 , 66 ], which is of interest in neurodegenerative processes of Alzheimer’s disease [ 52 ]. Furthermore, myelin is highly enriched in cholesterol, which is emerging with apolipoprotein E as an important factor in white matter impairment in aging and neurodegenerative diseases [ 6 , 8 , 69 ]. Axon damage (Fig.…”

Aerobic Exercise Facilitates the Nuclear Translocation of SREBP2 by Activating AKT/SEC24D to Contribute Cholesterol Homeostasis for Improving Cognition in APP/PS1 Mice

“…Cholesterol serves as a crucial constituent of myelin and synaptic vesicles, playing an indispensable role in synaptic plasticity as well as facilitating learning and memory processes within the brain [ 41 ]. Following neurodevelopment, cholesterol is unable to traverse the BBB and is primarily synthesized by astrocytes [ 11 ]. Compelling evidence suggests impaired cholesterol synthesis within the brain of AD patients [ 29 ], and intriguingly, abnormal deposition of cholesterol within tangled neurons has been observed in individuals with AD [ 6 ].…”

“…Following neural development, cholesterol encounters restricted permeability across the blood-brain barrier (BBB) [ 10 ]. In the brain, astrocytes primarily undertake the synthesis of cholesterol [ 11 ]. Sterol regulatory element-binding protein 2 (SREBP2), a transmembrane protein, assumes a pivotal role as a transcription factor in the regulation of cholesterol synthesis [ 12 ].…”

APPlications of amyloid-β precursor protein metabolites in macrocephaly and autism spectrum disorder

“…APP accumulation was more prevalent in mild cases of white matter ischemia compared to moderate and severe cases of white matter injury, suggesting that APP immunoreactivity occurs in the early stage of white matter lesions. Further, “recent studies have shown abnormal white matter in every AD brain” ( Sharp et al, 2023 ). Although the characteristic AD plaques and tangles are found in gray matter, increased Aβ 40/42 peptides damage myelin, causing cholesterol release and cholesterol dysmetabolism contributing to Aβ dysmetabolism, and a vicious injury cycle ( Sharp et al, 2023 ).…”

“…Further, “recent studies have shown abnormal white matter in every AD brain” ( Sharp et al, 2023 ). Although the characteristic AD plaques and tangles are found in gray matter, increased Aβ 40/42 peptides damage myelin, causing cholesterol release and cholesterol dysmetabolism contributing to Aβ dysmetabolism, and a vicious injury cycle ( Sharp et al, 2023 ).…”