Western diet as a trigger of Alzheimer's disease: From metabolic syndrome and systemic inflammation to neuroinflammation and neurodegeneration.

An excess of saturated fatty acids and simple sugars in the diet is a known environmental risk factor of Alzheimer's disease (AD) but the holistic view of the interacting processes through which such diet may contribute to AD pathogenesis is missing. We addressed this need through extensive analysis of published studies investigating the effects of western diet (WD) on AD development in humans and laboratory animals. We reviewed WD-induced systemic alterations comprising metabolic changes, induction of obesity and adipose tissue inflammation, gut microbiota dysbiosis and acceleration of systemic low-grade inflammation. Next we provide an overview of the evidence demonstrating that WD-associated systemic alterations drive impairment of the blood-brain barrier (BBB) and development of neuroinflammation paralleled by accumulation of toxic amyloid. Later these changes are followed by dysfunction of synaptic transmission, neurodegeneration and finally memory and cognitive impairment. We conclude that WD can trigger AD by acceleration of inflammaging, and that BBB impairment induced by metabolic and systemic inflammation play the central role in this process. Moreover, the concurrence of neuroinflammation and Aß dyshomeostasis, which by reciprocal interactions drive the vicious cycle of neurodegeneration, contradicts Aß as the primary trigger of AD. Given that in 2019 the World Health Organization recommended focusing on modifiable risk factors in AD prevention, this overview of the sequential, complex pathomechanisms initiated by WD, which can lead from peripheral disturbances to neurodegeneration, can support future prevention strategies.

The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain.

The elderly population is growing worldwide, with important health and socioeconomic implications. Clinical and experimental studies on aging have uncovered numerous changes in the brain, such as decreased neurogenesis, increased synaptic defects, greater metabolic stress, and enhanced inflammation. These changes are associated with cognitive decline and neurobehavioral deficits. Although aging is not a disease, it is a significant risk factor for functional worsening, affective impairment, disease exaggeration, dementia, and general disease susceptibility. Conversely, life events related to mental stress and trauma can also lead to accelerated age-associated disorders and dementia. Here, we review human studies and studies on mice and rats, such as those modeling human neurodegenerative diseases, that have helped elucidate (1) the dynamics and mechanisms underlying the biological and pathological aging of the main projecting systems in the brain (glutamatergic, cholinergic, and dopaminergic) and (2) the effect of defective glutamatergic, cholinergic, and dopaminergic projection on disabilities associated with aging and neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Detailed knowledge of the mechanisms of age-related diseases can be an important element in the development of effective ways of treatment. In this context, we briefly analyze which adverse changes associated with neurodegenerative diseases in the cholinergic, glutaminergic and dopaminergic systems could be targeted by therapeutic strategies developed as a result of our better understanding of these damaging mechanisms.

Western Diet Induces Impairment of Liver-Brain Axis Accelerating Neuroinflammation and Amyloid Pathology in Alzheimer's Disease.

Alzheimer's disease (AD) is an aging-dependent, irreversible neurodegenerative disorder and the most common cause of dementia. The prevailing AD hypothesis points to the central role of altered cleavage of amyloid precursor protein (APP) and formation of toxic amyloid-ß (Aß) deposits in the brain. The lack of efficient AD treatments stems from incomplete knowledge on AD causes and environmental risk factors. The role of lifestyle factors, including diet, in neurological diseases is now beginning to attract considerable attention. One of them is western diet (WD), which can lead to many serious diseases that develop with age. The aim of the study was to investigate whether WD-derived systemic disturbances may accelerate the brain neuroinflammation and amyloidogenesis at the early stages of AD development. To verify this hypothesis, transgenic mice expressing human APP with AD-causing mutations (APPswe) were fed with WD from the 3rd month of age. These mice were compared to APPswe mice, in which short-term high-grade inflammation was induced by injection of lipopolysaccharide (LPS) and to untreated APPswe mice. All experimental subgroups of animals were subsequently analyzed at 4-, 8-, and 12-months of age. APPswe mice at 4- and 8-months-old represent earlier pre-plaque stages of AD, while 12-month-old animals represent later stages of AD, with visible amyloid pathology. Already short time of WD feeding induced in 4-month-old animals such brain neuroinflammation events as enhanced astrogliosis, to a level comparable to that induced by the administration of pro-inflammatory LPS, and microglia activation in 8-month-old mice. Also, WD feeding accelerated increased Aß production, observed already in 8-month-old animals. These brain changes corresponded to diet-induced metabolic disorders, including increased cholesterol level in 4-months of age, and advanced hypercholesterolemia and fatty liver disease in 8-month-old mice. These results indicate that the westernized pattern of nourishment is an important modifiable risk factor of AD development, and that a healthy, balanced, diet may be one of the most efficient AD prevention methods.

Mechanisms of Anticholinesterase Interference with Tau Aggregation Inhibitor Activity in a Tau-Transgenic Mouse Model.

BACKGROUND: Symptomatic treatments of Alzheimer's Disease (AD) with cholinesterase inhibitors and/or memantine are relatively ineffective and there is a need for new treatments targeting the underlying pathology of AD. In most of the failed disease-modifying trials, patients have been allowed to continue taking symptomatic treatments at stable doses, under the assumption that they do not impair efficacy. In recently completed Phase 3 trials testing the tau aggregation inhibitor leuco-methylthioninium bis (hydromethanesulfonate) (LMTM), we found significant differences in treatment response according to whether patients were taking LMTM either as monotherapy or as an add-on to symptomatic treatments. METHODS: We have examined the effect of either LMTM alone or chronic rivastigmine prior to LMTM treatment of tau transgenic mice expressing the short tau fragment that constitutes the tangle filaments of AD. We have measured acetylcholine levels, synaptosomal glutamate release, synaptic proteins, mitochondrial complex IV activity, tau pathology and Choline Acetyltransferase (ChAT) immunoreactivity. RESULTS: LMTM given alone increased hippocampal Acetylcholine (ACh) levels, glutamate release from synaptosomal preparations, synaptophysin levels in multiple brain regions and mitochondrial complex IV activity, reduced tau pathology, partially restored ChAT immunoreactivity in the basal forebrain and reversed deficits in spatial learning. Chronic pretreatment with rivastigmine was found to reduce or eliminate almost all these effects, apart from a reduction in tau aggregation pathology. LMTM effects on hippocampal ACh and synaptophysin levels were also reduced in wild-type mice. CONCLUSION: The interference with the pharmacological activity of LMTM by a cholinesterase inhibitor can be reproduced in a tau transgenic mouse model and, to a lesser extent, in wild-type mice. Long-term pretreatment with a symptomatic drug alters a broad range of brain responses to LMTM across different transmitter systems and cellular compartments at multiple levels of brain function. There is, therefore, no single locus for the negative interaction. Rather, the chronic neuronal activation induced by reducing cholinesterase function produces compensatory homeostatic downregulation in multiple neuronal systems. This reduces a broad range of treatment responses to LMTM associated with a reduction in tau aggregation pathology. Since the interference is dictated by homeostatic responses to prior symptomatic treatment, it is likely that there would be similar interference with other drugs tested as add-on to the existing symptomatic treatment, regardless of the intended therapeutic target or mode of action. The present findings outline key results that now provide a working model to explain interference by symptomatic treatment.