A Mitocentric View of Alzheimer's Disease Suggests Multi-Faceted Treatments

Abstract

Alzheimer’s disease (AD) is defined by plaques made of amyloid-β peptide (Aβ), tangles made of hyper-phosphorylated tau proteins and memory deficits. Thus, the events initiating the cascade leading to these end points may be more effective therapeutic targets than treating each facet individually. In the small percentage of cases of AD that are genetic (or animal models that reflect this form of AD), the factor initiating AD is clear (e.g. genetic mutations lead to high Aβ1–42 or hyperphosphorylated tau proteins). In the vast majority of AD cases, the cause is unknown. Substantial evidence now suggests that abnormalities in Glucose metabolism/Mitochondrial function/Oxidative stress (GMO) are an invariant feature of AD and occur at early stage of the disease process in both genetic and non-genetic forms of AD. Indeed, decreases in brain glucose utilization are diagnostic for AD. Changes in calcium homeostasis also precede clinical manifestations of AD. Abnormal GMO can lead to plaques, tangles and the calcium abnormalities that accompany AD. Abnormalities in GMO diminish the ability of the brain to adapt. Therapies targeting mitochondria may ameliorate abnormalities in plaques, tangles, calcium homeostasis and cognition that comprise AD.

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…The prodromal stage encompasses the presymptomatic and mild cognitive impairment stages of AD. White line = progression of cognitive decline through the 5 stages of AD [11][12][13][14][15][16][17]. FDG-PET = fluoro-2-deoxyglucose positron emission tomography; MRI, magnetic resonance imaging adenosine triphosphate (ATP) production [9].…”

“…Multiple experimental paradigms, ranging from in vitro cell model systems and genomic analyses in animal models to postmortem autopsy of human brain and human brain imaging indicate deficits in mitochondrial function are consistent antecedents to AD development [11][12][13]24]. A decline in mitochondrial function can occur decades prior to clinical diagnosis of AD and thus may serve as a biomarker of AD risk, as well as a therapeutic target [12,24,32,67].…”

“…1). Dysfunctions in glucose metabolism, bioenergetics, and mitochondrial function are consistent antecedents leading to AD pathology, including Aβ plaque and neurofibrillary tangles [11]. Dysfunctional mitochondria produce high levels of reactive oxygen species (ROS); these ROS can negatively affect specific mitochondrial components, including mitochondrial DNA (mtDNA), membrane lipids, and oxidative phosphorylation proteins [18,19].…”

Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders

“…Dysfunction in glucose metabolism, bioenergetics, and mitochondrial function are consistent antecedents to the development of Alzheimer pathology [52,[91][92][93]. A decline in brain glucose metabolism and mitochondrial function can appear decades prior to the onset of histopathological and/or clinical features and thus may serve as a biomarker of AD risk as well as a therapeutic target [94][95][96][97].…”

Dysregulation of Ca²⁺ Homeostasis in Alzheimer’s Disease: Role in Acetylcholinesterase Production and AMPA Receptor Internalization

“…A ␤ may also alter neuronal excitability and calcium homeostasis [7] , disrupt mitochondrial function and increase oxidative stress [8] , activate inflammatory mechanisms [9] and caspases [10] , increase tau phosphorylation [11] and induce apoptosis [12] . The relative contribution of these mechanisms to cognitive decline in AD is unclear.…”