PARTICLE

 Save as PDF

Abstract

Memory naturally declines as we age, but the rapid loss of memory can be distressing for people living with Alzheimer’s disease (AD). How memories are formed and retrieved in the brain is not fully understood; it is thought to require plasticity to the synapses connecting neurons in a network of engram cells. Plasticity may occur either through changes to the volume and location of molecules and organelles within the synapse, or gross structural changes of synapses. Memory naturally declines as we age, as do many of the mechanisms required for learning and memory, such as changes in concentrations of the cytoskeletal structural protein Microtubule-Associated Protein Tau, reduced brain glucose metabolism, and sensitivities to insulin. The biggest risk factor for developing AD is ageing, yet only few studies try to reconcile the natural decline in functions we see with ageing with the dramatic impairment of these pathways in AD, such as Tau protein and energy homeostasis by neurons. This review will therefore explain the changes to metabolism, Tau protein, and memory impairment during ageing, and explore the latest research that links these processes to neurodegeneration seen in AD, and other Tauopathies. Understanding how ageing and dementia diverge may offer an important and underutilised avenue for therapeutic interventions to target metabolism in both “healthy” ageing and disease.

Keywords

Alzheimer’s disease, Tau, ageing, metabolism, memory, glucose, lifestyle

INTRODUCTION

Ageing is the strongest risk factor for dementia^[1,2]. Episodic memory and many cognitive functions are known to decline progressively with ageing. Alzheimer’s disease (AD)-related cognitive decline occurs more rapidly from a critical age than in healthy ageing, whereas vascular dementia, primarily associated with major stroke, causes a rapid then steady decline^[3]. Numerous processes are known to be affected by ageing, including glucose metabolism, insulin resistance^[4], inflammation (termed “Inflammageing”)^[5], protein translation^[6,7], and protein concentrations such as that of AD-associated microtubule-associated protein Tau (Tau)^[8,9].

As commonly quoted, despite accounting for 2% of body mass, the brain requires ~20% of the energy generated through oxidative metabolism^[10]. Most of this energy is accounted for in regions of highly active neurons through synaptic function and restoration of neuronal membrane potentials^[11]. Memory and problem-solving are therefore energetically expensive brain functions as they require temporally and spatially specific patterns of neuronal activity.

To understand how metabolism links to cognitive functions, it is important to know the pathways that neurons can use for energy. Neurons can perform the metabolism of glucose through mitochondrial oxidative phosphorylation (OXPHOS) or cytosolic aerobic glycolysis (nonoxidative metabolism of glucose despite the presence of abundant oxygen). OXPHOS is the most efficient pathway for producing energy in the form of 36 ATP, as compared to 2 ATP in aerobic glycolysis. A disadvantage of OXPHOS is associated with the free radical hypothesis, which suggests that reactive oxygen species from OXPHOS damage biomolecules and cause ageing^[12,13]. Aerobic glycolysis has been shown to occur in neuronal somata to provide the energy required for neurons to function at rest or during neuronal activity, despite oxygen being available for OXPHOS^[14,15]. Glycolysis is known to be required during high energy expenditure, such as long-term memory formation^[16,17]. Traditionally, aerobic glycolysis was seen to compensate for the limited ATP production by rapid glucose metabolism. However, more recently, it is thought to produce metabolites for the building blocks of biosynthesis required for differentiation, and growth such as synaptic plasticity^[18–20]. Neurovascular coupling allows neurons to control the vasodilation of blood vessels to maintain oxygen and glucose requirements. However, the limit of blood supply to the brain means that glucose stored as glycogen can also be metabolised for energy. Due to the storage of glycogen in astrocytes, the astrocyte-neuron lactate shuttle has been hypothesised. In response to glucose sensing, astrocytes can upregulate glycolysis into lactate, which can be shuttled from astrocytes to neurons. The use of this lactate is unknown, but it has been suggested to be metabolised through OXPHOS^[21]. However, astrocytes also perform aerobic glycolysis, which is stimulated by glucose and glutamate uptake into astrocytes; this mechanism directly couples neuronal activity to aerobic glycolysis^[22,23]. In addition, when blood glucose level is low, such as during intense exercise, fasting, or diabetes, ketone bodies can be metabolised for energy. Although controversial, “ketogenic diets” have been suggested for multiple neurological disorders and epilepsy, in particular to mimic fasting and reduce neuronal activity and lactate concentrations^[24–26].

One hypothesis is that mitochondrial impairment may shift energy consumption from oxidative phosphorylation towards glycolysis or ketolysis^[27]. Mitochondrial impairment, through numerous mechanisms, has been linked to many neurodegenerative conditions (for Review^[28]). However, the shift towards aerobic glycolysis can be a cell proliferation process, or can occur in cancer in the presence of healthy mitochondria^[29,30]. It therefore raises the question of how might alterations in energy metabolism influence memory impairment and pathology seen in neurodegeneration. This review will address two main aspects. First, it will delve into how metabolism may alter the function and homeostasis of Tau, a protein required for cytoskeletal structure^[31], which has more recently been shown to bind with synaptic vesicles, mitochondria, and ribosomes^[32]. In Taopathies such as AD and frontotemporal dementia, Tau forms pathological aggregates. Thus, understanding the links between metabolism and the physiological or pathological roles of Tau holds important therapeutic potential. Secondly, it will explore how metabolism and its influence on Tau protein can feed back to memory impairment. This review will therefore focus on how links established in the first aspect between metabolism and Tau could trigger the memory impairments observed in Tauopathies.

METABOLIC DEFICITS AND TAU PATHOLOGY

It has been debated whether Tau pathology causes metabolic deficits or metabolism can directly influence Tau pathology. During ageing, there is a progressive hypometabolism of glucose in the brain. Even greater glucose hypometabolism in the hippocampus can predict the progression to late-onset AD and mild cognitive impairment (MCI) compared with age-related cognitive impairment^[33,34]. AD is characterised by decreased cortical^[35] and hippocampal^[33] glucose metabolism that is thought to reflect reduced synaptic activity^[36]. Reduced cerebral glucose metabolism is also seen in young cognitively normal carriers of the late-onset genetic risk factor for AD, Apolipoprotein Ε4 (ApoE4). ApoE4 also exacerbates Tau-mediated pathology^[37,38]. Figure 1 shows the relationship between glucose consumption and cognitive function with age; Tau Cerebrospinal fluid (CSF) concentration is superimposed^[3,33,39,40]. In several studies, glucose hypometabolism follows a similar anatomical progression to the Braak stages of AD, and Tau pathology seen in Progressive Supranuclear Palsy and Corticobasal Degeneration^[41–43]. However, it is noted that variations in the age of disease onset may have caused discrepancies between studies^[44–47]. Furthermore, Tau pathology and glucose hypometabolism were shown to correlate with cognitive decline^[48]. No correlation exists between amyloid-β pathology and cognitive impairments^[49].