1. Introduction
Obesity is a multi-factorial pathological state that may be related to altered
nutritional behavior or may occur secondary to genetic, endocrine, iatrogenic, or
hypothalamic diseases [1]. Specifically, a body mass index of 30 kg/m2 or
higher is the criterion for the diagnosis of obesity [2]. A study by the Global
Burden of Disease Group reported in 2017 that “since 1980, the prevalence of
obesity has doubled in over 70 countries and has continuously increased in most
other countries” [3]. Obesity is associated with the development and progression
of many diseases, such as type II diabetes mellitus [4].
Alzheimer ’s disease (AD) is the most common cause of senile dementia, and the
main pathological features of AD are the deposition of -amyloid
(A) protein in the brain, which leads to the formation of senile
plaques, and excessive phosphorylation of the Tau protein, leading to the
formation of neurofibrillary tangles and massive loss of neurons [5]. Studies
have shown a significant correlation between obesity and AD, and obesity is
considered as a risk factor for AD [6]. For example, a study of 293 subjects
found that individuals with obesity had a significantly higher probability of
dementia than individuals who did not have obesity [7]. Interestingly, the age of
people with obesity was associated with their risk of dementia, as a 40-year
follow-up study of 1152 subjects found that overweight in middle-aged individuals
increased their risk of dementia in later years [8]. Conversely, controlling the
weight of middle-aged people can reduce the incidence of AD: a cohort prediction
model based on the Australian population showed that the proportion of dementia
in the age group 65–69 years would decrease by 10% by 2050 if the percentage of
middle-aged individuals with obesity decreased to 20% between 2015 and 2025 [9].
A number of animal experiments have also reported similar results. High-fat diet
(HFD) was found to increase the weight of wild-type and AD transgenic animals,
and decrease memory and spatial learning abilities in behavioral experiments
[10, 11, 12]. These findings indicate that obesity accelerates the progression of
disease in AD-susceptible individuals or induces the occurrence of AD in low-risk
individuals.
According to the pathological mechanism of AD and the existing research results,
the main mechanism of obesity that is associated with an increase in the
prevalence of AD is the promotion of A accumulation. However, the exact
mechanism is not completely clear. Obesity-induced disruptions in metabolic
mechanisms may lead to A accumulation, but these mechanisms have not
been reviewed so far. In order to shed light on the potential mechanisms, the
present paper conducts a theoretical analysis of the mechanism of obesity-induced
metabolic disorders associated with A based on relevant research
conducted in recent years.
2. Obesity-induced Promotion of A Accumulation
A is derived from the metabolism of the amyloid precursor protein, and
it is eliminated via degrading enzymes and other pathways. A can
regulate synaptic transmission under normal physiological conditions, but certain
pathological conditions affect the production and clearance of A. This
can lead to the accumulation and deposition of A and, subsequently, the
formation of senile plaques and various neurotoxic effects [13, 14].
Obesity has been found to promote A accumulation in the central nervous
system. In some experimental studies, compared with the normal diet group,
animals including rats and AD transgenic mice that were fed a HFD were found to
have significantly higher levels of A in the cerebral cortex,
hippocampus, and serum [15, 16, 17]. Furthermore, Wakabayashi et al. [18]
reported that when HFD treatment was increased from 2 months to 12 months,
A concentration in the cerebral cortex and hippocampus of
insulin-resistant AD mouse models gradually increased, amyloid plaques appeared,
and the plaque-containing areas gradually expanded. In addition, Thériault
et al. [19] and Lin et al. [20] reported in separate studies
that transgenic mice on HFD treatment showed an obvious increase in A
levels and deposition in the brain microvascular components, hippocampus
microcirculation, and cortical branch of the middle cerebral arteries. Cellular
experiments have also validated the effect of excessive caloric intake on
A levels; for example, Yang et al. [21] found that high sugar
intake increased the production of A in human neuroblastoma cells (that
is, SH-SY5Y cells). Excessive HFD intake has also been found to affect the health
of offspring. For example, studies have shown that A40 and
A42 levels in the hippocampus and the plasma
A42/A40 ratio were significantly higher, and the
hippocampus A plaque load levels were also higher, in AD transgenic mice
born to mothers on HFD during pregnancy and lactation than in mice born to
mothers that were fed a normal diet [22]. Currently, overweight and obesity
affect more than an estimated 2.1 billion adults, and 38% of these are women of
childbearing age [23]. This implies an increased risk of AD in the next
generation in the form of earlier onset of AD or a higher incidence of AD.
Therefore, it is important to understand the mechanisms by which obesity leads to
A accumulation in order to develop appropriate prevention and treatment
strategies.
3. Obesity-induced Metabolic Disorders and A Accumulation
3.1 Insulin Resistance and A Accumulation
In recent years, many researchers have conducted epidemiological studies on the
relationship between obesity, type II diabetes mellitus, and AD. Although the
types of studies, the selection of research objects, and the controlled
confounding factors are different, as are the risk ratios reported by the various
studies, they all confirm that obesity is the main trigger of type II diabetes
mellitus and that type II diabetes mellitus is a risk factor for AD [24, 25, 26, 27, 28, 29].
Insulin resistance is one of the main characteristics of type II diabetes
mellitus. Insulin is an important hormone for reducing blood glucose levels in
the human body and plays an important role in neuronal survival and the
maintenance of brain function. Insulin is necessary for neuronal synaptic
plasticity and facilitates learning and memory [30, 31]. Insulin can be degraded
and inactivated by insulin-degrading enzyme (IDE) [32]. IDE is also an important
A-degrading enzyme, but compared with A, insulin has a stronger
affinity for IDE [33, 34]. When insulin resistance occurs in patients with
diabetes, insulin levels in the body are relatively high and IDE is heavily bound
to insulin. This reduces the degradation of A. This mechanism by which
IDE-induced A degradation is reduced as a result of the binding of IDE
by high levels of insulin was demonstrated by Karczewska-Kupczewska et
al. [35], who injected high-dose insulin into 20 healthy young volunteers and
found that their plasma A concentrations increased.
In patients with type II diabetes, the increase in blood glucose levels leads to
an increase in the levels of advanced glycation end products (AGEs) [36]. AGEs
refer to the stable and irreversible end products formed by the binding of the
aldehyde group of fructose, glucose, and other reducing sugars with the amino
group of proteins, nucleic acids, amino acids, and other macromolecular
substances after a series of complex reactions under non-enzymatic conditions.
AGEs can accumulate in the body and participate in the occurrence and development
of diabetes, AD, and other diseases through oxidative stress and induction of
inflammation. Accordingly, Ko et al. [37, 38] found that AGEs
can cause an increase in A through the oxidative stress pathway
in vitro and in vivo. Therefore, AGE-induced oxidative and
inflammatory mechanisms may also explain the increase in A levels in
patients with diabetes.
Type II diabetes mellitus and AD are important public health problems globally,
and the prevalence of both diseases is increasing every year, posing a heavy
burden on families and society. Epidemiological studies have confirmed that the
two conditions are closely related and have many common clinical features and
pathogenesis, such as IDE and AGEs. These similar features could be potential
drug targets for both the prevention and treatment of type II diabetes mellitus
and AD, and are an important direction for further research in the future.
3.2 Metabolic Inflammation and A Accumulation
In 2006, Hotamisligil first proposed the concept of “metabolic inflammation”
[39]. It is described as a chronic subclinical inflammation induced by metabolic
disorders under conditions of excess nutrition and energy. Obesity can cause
metabolic inflammation and induce an increase in the levels of pro-inflammatory
cytokines, mast cells, T cells, and macrophages [40, 41], which can activate many
key stress responses and affect important metabolic processes, such as insulin
signal transduction [42]. In wild-type and transgenic mice experiments, HFD was
found to induce central and peripheral inflammation, which was manifested as
increased expression of pro-inflammatory cytokines such as tumor necrosis factor
(TNF)- and interleukin (IL)-6 [43, 44]. With regard to in vitro experiments,
Sutinen et al. [45] induced the differentiation of SH-SY5Y cells into
neuron-like cells and exposed them to IL-18, and found that
A production was increased. IL-18 is an inflammatory cytokine produced
by adipose tissue and is positively correlated with the degree of obesity. In the
central nervous system, IL-18 binds to its receptor and produces a complex
intracellular cascade, which may be one of the apoptosis-inducing factors that
leads to neurodegeneration in the progression of AD. Microglia can bind and clear
A fibrils via cell surface receptors after activation. So et
al. [46] showed that HFD caused microgliosis in the hippocampus and cortex of AD
and wild-type (WT) mice. While this can assist in the clearance of A,
sustained microglial activation can lead to the release of pro-inflammatory
cytokines, exposure to these cytokines leads to the down-regulation of genes with
roles in A clearance. Thus, obesity-induced metabolic inflammatory
pathways may also be important mediators of AD and need to be examined in depth
in future research.
3.3 Nonalcoholic Fatty Liver Disease and A Accumulation
Obesity is commonly associated with non-alcoholic fatty liver disease (NAFLD)
[43, 47], which is characterized by the accumulation of lipids in hepatocytes and
accompanied by hepatocellular damage and inflammatory response of varying
degrees, and is considered to be a manifestation of metabolic disorder. Impaired
peripheral clearance is one of the characteristics of NAFLD. As the main
scavenger of peripheral A, the liver promotes the outflow of A
from the brain by scavenging peripheral A and plays an important role in
maintaining the balance between brain A and plasma A. Thus, the
reduction in the plasma clearance of A during NAFLD indirectly affects
A clearance in the brain [48, 49, 50]. The scavenging effect of liver on
A is closely related to low-density lipoprotein receptor-associated
protein 1 (LRP1). LRP1 is highly expressed in hepatocytes and is the main cell
surface receptor involved in A clearance, and it can degrade A
in the liver. LRP1 in the liver is highly vulnerable to certain pathological
processes, including the inflammatory response, which can result in a reduction
in A degradation in the liver [51, 52, 53]. Further, pro-inflammatory
cytokines and inflammation play an important role in promoting the development of
NAFLD and, consequently, the increase in A levels [54, 55]. Thus, the
pro-inflammatory mechanisms of NAFLD may shed light on the obesity-induced
A accumulation and warrant further investigation.
4. Intestinal Microbiota and A Accumulation
A two-way interaction has been observed between the central nervous system and
the intestinal microbiota: the central nervous system induces changes in the
composition of the intestinal microbiota by regulating intestinal peristalsis and
secretion, and the intestinal microbiota can affect the central nervous system
through endocrine, metabolic, and immunity-related pathways. The two systems are
closely linked and affect each other via what is referred to as the “gut-brain
axis” [56, 57, 58]. Therefore, maintaining the balance of intestinal microbiota can
help maintain normal functioning of the central nervous system, while any
imbalance in the intestinal microbiota can promote the development of diseases of
the central nervous system such as Parkinson’s disease and AD [59]. The
composition and abundance of intestinal microbiota are closely related to the
host’s diet, medication use, and metabolism. When the host’s food intake changes
abnormally, the balance of intestinal microbiota may be destroyed. Many studies
have shown that obesity can induce an imbalance in the intestinal microbiota
[60, 61, 62]. Kim et al. [63] found that HFD treatment of mice resulted in an
increase in A levels in the hippocampus and cortex, an increase in
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) levels, a
decrease in the diversity of intestinal microflora in the feces, a decrease in
butyrate-producing bacteria and sodium butyrate levels in the blood, and an
increase in total cholesterol levels. They also confirmed in cell experiments
that high cholesterol levels caused an increase in A levels through the
nuclear factor-B (NF-B)/NOX2/reactive oxygen species (ROS)
pathway, while sodium butyrate had antioxidant effects that inhibited the above
pathway and reduced A levels. Based on these findings, it was speculated
that an increase in A in the hippocampus and cortex may be associated
with an imbalance in intestinal microbiota and a decrease in butyrate levels
caused by obesity. The research results of Tedelind et al. [64] also
confirmed that butyrate had inhibitory effects on NF-B, IL-6, and
TNF-. As a result of all these findings, the gut-brain axis is now an
important direction in AD research; in particular, further studies are needed on
whether obesity causes other changes in the intestinal microbiota that can
promote AD development.
Obesity, type II diabetes mellitus, and NAFLD are considered as
components of the metabolic syndrome (MS). Insulin resistance is believed to be
the common pathological basis of MS, and inflammation is also closely related to
MS. Additionally, imbalance in intestinal microbiota is associated with diseases
such as obesity and is the key environmental factor that leads to MS. Thus, the
coexistence of these factors, that is, intestinal microbiota imbalance, obesity,
insulin resistance, and MS, and their influence on each other, may promote an
increase in A levels and the development of AD and, therefore, their
underlying mechanisms warrant further research to improve our understanding of
AD.
5. Other Factors Associated with A Accumulation in Obesity
Interestingly, researchers have also found other possible mechanisms by which
obesity causes an increase in A. Cytochrome P450 1B1 (CYP1B1) is a
monooxygenase that belongs to the second subfamily of the first family of the
cytochrome P450, and is involved in the metabolism of various substances such as
fatty acids. Yang et al. [65] found that CYP1B1 gene knockout
in mice prevented A aggregation in the hippocampus and learning and
memory disorders caused by HFD; thus, A aggregation induced by HFD may
be related to the CYP1B1 pathway.
MicroRNAs are a class of small-molecule single-chain non-coding RNAs that can
regulate gene expression after transcription. The microRNA miR-7 is abundant in
the brain and can affect A metabolism. In fact, the expression of miR-7
has been found to be significantly increased in the cerebral cortex of AD
patients. Accordingly, the expression of miR-7 was found to significantly
increase in the brain of mice with diet-induced obesity; this impaired the
removal of A by microglia and, thus, caused an increase in A
levels [66].
The -secretase 1 (BACE1) cleaves amyloid precursor protein (APP)
through an amyloidogenic pathway and it is an essential enzyme for the generation
of A. Francesca Natale et al. [67] found that maternal HFD
altered the expression of BACE1 genes and enhanced A deposition in the
hippocampus of the offspring, the AD transgenic mice born to overfed mothers
showed an impairment of synaptic plasticity and cognitive deficits earlier than
controls.
However, some studies have shown opposite results. For example, a study by
Amelianchik et al. [68] showed that feeding a HFD to AD transgenic mice
starting at or before 3 months of age slowed A deposition and cognitive
decline compared to AD transgenic mice on a regular diet. Elhaik Goldman et al.
[69] published a study showing that HFD had no effect on the level of
A42 in the cortex of AD transgenic mice. Further experiments are
needed in the future to provide more evidences and explore the mechanisms.
6. Conclusions
The various research findings mentioned above indicate that there is probably
positive correlation between HFD/obesity and A accumulation. The
underlying mechanisms mainly involve metabolic diseases, such as type II
diabetes, and an imbalance in the gut microbiota (Fig. 1).
Fig. 1.
Mechanisms underlying obesity-induced A accumulation in
Alzheimer’s disease. IDE, insulin-degrading enzyme; AGEs, advanced glycation end
products; NAFLD, non-alcoholic fatty liver disease; A,
-amyloid; LRP1, lipoprotein receptor-associated protein 1; CYP1B1, Cytochrome P450 1B1; BACE1, -secretase 1.
Nevertheless, inhibition of A production or antagonizing its effects
may counteract synaptic dysfunction, as well as memory and cognitive impairment,
caused by the increase in the production and deposition of A [17]. In
fact, reversal of the cognitive impairment caused by HFD has been demonstrated in
rats on HFD treatment for 6 months that received a single hippocampal injection
of A33-42 antibodies 24 h before a behavioral test [70]. Other
animal experiments have also shown that calorie restriction can inhibit weight
gain in mice, improve peripheral and central insulin sensitivity, and
significantly reduce A deposition in the brain [18]. Additionally, Kim
et al. [43] found that when mice fed a HFD for 2 months returned to a
normal diet for 3 months, the number and area of A plaques decreased
significantly. This indicates that early dietary correction (before the
appearance of signs of late AD) can reduce the pathological changes associated
with AD. Further, increasing exercise was found to have the same effect, as some
studies found that exercise training during HFD feeding in mice could effectively
intervene in A accumulation and reduce memory deficits induced by HFD
[71]. Exercise can enhance the activity of neprilysin, a type II membrane protein
located on the surface of the cell that is also an A-degrading enzyme,
and this can effectively inhibit A accumulation and memory deficits
induced by HFD [72]. Further, controlling diet and increasing exercise can also
help to improve the symptoms of NAFLD and, thereby, reduce the accumulation of
A [73]. Thus, based on current knowledge, as a risk factor for AD,
obesity can be improved through dietary adjustments and increased physical
exercise. Accordingly, the World Health Organization considers that modifiable
risk factors, such as diet, are a significant factor in AD prevention.
A accumulation is an early event of AD and is often considered as the
initiation factor for the occurrence and development of AD. Preventing the
accumulation of A may be more impactful than trying to reverse an
already existing AD pathology [74, 75]. Reducing calorie intake or persisting
with exercise may be beneficial in reducing or reversing early AD pathological
changes.
Author Contributions
BZ and WW contributed to the conception of the study. WW and SMH searched and sorted references. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
Ethics Approval and Consent to Participate
Not applicable.
Acknowledgment
Thanks to all the editors and the peer reviewers for their opinions and suggestions.
Funding
This work was funded by the National Natural Science Foundation of China (No. 81873108) and the Traditional Chinese Medicine Scientific Research Project in Heilongjiang Province (No. ZHY2022-118).
Conflict of Interest
The authors declare no conflict of interest.
