Neurochemical Aspects of Alzheimer’s Disease and Movement Disturbances: A Theory of β-Amyloid and τ-Protein

Abstract

The pathologic and molecular substrate of people diagnosed with cognitive deficits and movement disturbance may not occur exclusively in the context of a brain region, but it may be expressed in another part of body such as muscle. A large body of research has demonstrated that slow motor performance is associated with cognitive impairment in elderly people. The interdependence between motor dysfunction and cognition decline is still not fully understood. Although several factors have been suggested to give a plausible explanation, β-amyloid (Aβ) and τ-protein aggregation is a common feature of a number of neurodegenerative disorders which are characterized by both motor and cognitive impairment, and it is assumed that the aggregation process plays a central role in the pathogenesis of cognitive impairment and motor dysfunction in Alzheimer’s disease. The purpose of the present review is to provide an overview of the available evidence that can help to better elucidate the pathophysiological mechanisms underlying the relationship between cognitive and movement disturbances by focusing on Aβ and τ-protein.

Introduction

Alzheimer’s disease (AD) is characterized by cognitive impairment attributed to progressive loss of motor functions at various stages of the illness, and aging is a key risk factor for disease onset. Understanding the mechanisms and biological pathways linking risk factors to cognitive impairment and motor function disturbances may enable the development of early diagnostic tools and effective therapies. A large body of research has demonstrated that slow motor performance is associated with cognitive impairment and dementia in elderly people. ^{1 –3} The exact mechanisms underlying the association between cognition decline and motor dysfunction are still not fully understood. Although several factors have been suggested to give a plausible explanation, β-amyloid (Aβ) and τ-protein aggregation is a common feature of a number of neurodegenerative disorders which are characterized by both motor and cognitive impairment, and it is assumed that the aggregation process plays a central role in the pathogenesis of cognitive impairment and motor dysfunction in AD. A better understanding of the relationship between cognitive impairments and motor function impairments in elderly people can help address a number of practical concerns such as identification of those individuals at highest risk of falling, development of rehabilitation, and training programs to address ambulation under conditions requiring more cognitive control. The purpose of the present review is to provide an overview of the available evidence that can help to better elucidate the pathophysiological mechanisms underlying the relationship between cognitive and motor function disturbances by focusing on Aβ and τ-protein.

Cognition and Motor Functions

Cognition and motor functions are functionally connected, both are controlled by brain areas such as frontal lobes, cerebellum, hippocampus, and basal ganglia. They collectively interact to exert governance and control over executive function, attention, and visuospatial function, as well as the motor processing functions. Therefore, the same mechanisms that underlie decline in cognitive functioning may be associated with decline in motor functions. A growing body of evidence confirms that motor slowing precedes and may predict the onset of cognitive impairment. ^{1 –3} Etiologies are unclear but may include pathological changes caused by the accumulation of abnormally folded Aβ and τ-protein in the muscles of patients with AD. However, the time at which this motor impairment begins in relation to the onset of cognitive impairment is not clear. In a longitudinal cohort study conducted by Buracchio and colleagues demonstrated that individuals who were older than 65 years in the general population converting to mild cognitive impairment (MCI) showed more rapid declines in gait compared to participants who did not convert to MCI, and the decrease in gait speed accelerates up to 12 years prior to MCI emergence. ⁴ In a different analysis involving 681 community-dwelling older adults, worse stages of cognitive impairment were shown to be associated with poorer ability to increase speed and walk quickly. ⁵ Moreover, it is reported that the change in spatiotemporal gait parameters and balance with age is associated with the appearance of cognitive impairments. ⁶ Achache et al suggest that slow gait precedes cognitive decline.

τ-Proteins and Movement Disorders

Aggregates of τ-protein are part of the pathological process of a number of neurodegenerative disorders which are characterized by both motor and cognitive impairment. They are consistently found in AD, amyotrophic lateral sclerosis/parkinsonism–dementia complex of Guam, corticobasal degeneration, postencephalitic parkinsonism, progressive supranuclear palsy, Pick’s disease, argyrophilic grain disease, Gerstmann-Straussler-Scheinker syndrome, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease, subacute sclerosing panencephalitis, normal pressure hydrocephalus (NPH), and in other rare conditions. ⁶ These associations suggest that motor performance is impacted by τ-protein aggregation. τ-Protein aggregation into intraneuronal filamentous inclusions is the most obvious pathological event in neurodegenerative disorders. In AD, τ pathology is observed at the microscopic level in pyramidal cells of the hippocampus, the entorhinal cortex, and the supragranular (II-III) and infragranular (V-VI) layers of the association cortical areas. ^{7 –9} Many cortical and subcortical areas, such as nucleus basalis of Meynert, amygdala, locus coeruleus, and dorsal aphe, are also affected by τ-protein. ⁷ In frontotemporal dementias, τ generally deposits in the frontal and temporal lobes. ¹⁰ In Parkinson disease, one study reported that the number of neurofibrillary tangles in the substantia nigra was significantly associated with gait impairment in older persons with and without dementia. ¹¹ The association between τ-protein and movement disturbances has also been found in other studies conducted in patients with AD and NPH. ^{12 –14} In a number of experimental studies, τ transgenic mouse models showed a decline in motor function and reduced performance in sensorimotor tasks, like beam walking or inverted grip hanging, as well as the development of a hind limb clasping phenotype. ^{15 –18} Ultrastructural analyses of human mutant τ (P301L) transgenic mice showed axonal swellings resembling spheroids in human tauopathies in both gray and white matter, which were filled with τ-immunoreactive filaments and autophagic vacuoles. ¹⁹ Analysis of the spinal cord motor neuron number in transgenic mice for human mutant τ reveals a dramatic decrease of approximately 50%. ²⁰ However, accumulating evidence suggests that motor functions are impacted by τ aggregation both in diagnosed and prodromal disease.

Exercise and τ-Proteins

The benefits of physical exercise on the neurodegenerative process in τ-protein are well recognized but not well understood. A recent study by scientists in the United States found that exercise improved general locomotor and exploratory activity in transgenic mice and resulted in significant reductions in full-length and hyperphosphorylated τ in the spinal cord and hippocampus. ²¹ This finding is consistent with the results published by García-Mesa and colleagues, ²² who reported a reduction of τ pathology in the hippocampus and cerebral cortex of exercised 3xTransgenic AD mice. In 2 other studies, exercise prevented both the development of hippocampal τ pathology and memory impairment and significantly reduced τ phosphorylation in transgenic mice expressing pathogenic τ. ^23,24 These findings indicate that the progression of τ pathology was attenuated by exercise. Hyperphosphorylation and aggregation of τ are associated with hippocampal synapse loss and impaired synaptic function, ²⁵ so it is possible that exercise prevented these alterations in the spinal cord, restoring adequate neurotransmission at the neuromuscular junction. Exercise elevates the expression of synaptophysin and synapsin 1, ²⁶ supporting the notion that exercise enhances synaptic neurotransmission. A reduction in τ pathology via exercise could result in an increase in expression of synaptic proteins, or this increase could occur directly via forced exercise, resulting in enhanced synaptic transmission in the spinal cord and improved locomotor function. This fact is also in accordance with recent clinical evidence, ^27,28 showing that a patient diagnosed with corticobasal degeneration and progressive supranuclear palsy who participated in a regular exercise program for 10 years displayed reduced fall frequency, as well as improved balance and ambulation after exercise training. ²⁸

β-Amyloid and Movement Disorders

Several recent studies have reported an association between Aβ and decreased mobility in normal and mildly cognitively declined older adults. Cross-sectional analyses on 91 elderly patients (41 cognitively normal elderly participants, 25 cases with MCI, and 25 patients with mild AD) demonstrate a pattern of diminished motor control related to cognitive status. This study concludes that motor/psychomotor decline represents an integral part of the earliest manifestations and stages of AD, especially dysfunction in motor tasks. ²⁹ Taken together, these results indicate that complex motor function is mediated by brain regions affected in incipient and early AD which are distinct from those areas involved in less complex motor control and in memory and language. These findings are in line with prior reports of declining gait speed in patients with MCI and in healthy adults converting to MCI years later. ⁴ Recent research has revealed a significant association between gait speed and brain Aβ in a group of elderly individuals at high risk for dementia, in the putamen was the region most strongly associated with slower gait speed, suggesting that Aβ in these regions disrupts motor circuitry thereby impacting gait. ³⁰ A more recent study found that people with greater Aβ deposition displayed increased fall risk over a 12-month period follow-up. These results indicate that coexisting Aβ plaque deposition may play a role in subsequent cognitive and mobility decline in older adults. ³¹ Another study reported slower gait speed, lower cadence, longer double support time, and greater stance time variability in older adults with high cerebral amyloid deposition, in the temporal lobe was the region most strongly associated with all gait parameters. ³² More recently, an amyloid imaging study shows that Aβ deposition is associated with gait variability. Associations are localized in motor-related cortical and subcortical regions. ³³

This is supported by studies that have identified impaired static and dynamic balance, mobility, and gait dysfunction in early AD ³⁴ This concurs with previous literature, a study in healthy community-dwelling older adults, which found that higher Aβ was associated with faster time to first fall over 12 months. ³⁵ The topographical distribution of Aβ deposition and its relation to movement disorders was mapped in 2 autopsy studies; Aβ deposition was observed in the midfrontal, superior temporal, inferior parietal, and entorhinal cortices and hippocampus. ^36,37 Another study found greater Aβ deposition in the putamen, caudate, precuneus, and occipital, temporal, and parietal lobes, and the association between movement and Aβ deposition was strongest in the posterior putamen. ³⁸ Given is proximity to the motor corticostriatal circuits. ³⁹ Furthermore, a motor behavioral analysis in amyloid precursor protein (APP) transgenic mice showed significant impairment in a variety of tasks relying on motor performance, like balance beam, string suspension, or rotarod, as well as a decline in memory tasks. ^40,41 Axonal transport defects were detected in the spinal cord, accompanied by severe axonal defects in various brain regions including cortex, hippocampus, or striatum in APP transgenic mice. ⁴² Interestingly, these axonal defects manifested approximately a year before the typical disease-related pathology. ⁴³ This evidence suggests that Aβ deposition contributes to movement disorders.

Exercise and Aβ

Exercise training has proven to reduce the risk of AD as well as decrease Aβ production. Studies in animal models such as transgenic mouse models of AD demonstrate that exercise reduces the load of Aβ plaques in the hippocampus and cortex. ^43,44 In another study, 20 weeks of exercise demonstrated significantly improved cognitive function and reduced the expression of Aβ-42 in APP/presenilin-1 transgenic mice. ⁴⁵ Ten-week exercise was also found to be associated with decreased Aβ burden, reduced neuronal loss, increased hippocampal neurogenesis, and reduced spatial memory loss in transgenic mouse models of AD. ⁴⁶ In addition, exercise is reported to enhance neurogenesis and results in increased numbers of synapses per neuron. ⁴⁷ Moreover, exercise induced increase in the expression of brain-derived neurotrophic factor (BDNF), which regulates neuronal development as well as plasticity. ⁴⁸ More recent evidence demonstrates that exercise and BDNF reduce production of toxic Aβ peptides through a mechanism involving enhanced α-secretase processing of APP. ⁴⁹ Another possible mechanism suggested by animal experiments is that exercise may thus inhibit Aβ production via upregulation of SIRT-1, which biases APP processing toward the nonamyloidogenic pathway. ⁵⁰

The Correlation Between Aβ and τ-Protein

Alzheimer’s disease is microscopically characterized by the presence of extracellular senile plaques primarily composed of Aβ peptide and intracellular neurofibrillary tangles constituted by hyperphosphorylated aggregates of the microtubule-associated protein τ, whose accumulation ultimately leads to extensive neuronal loss and progressive decline of cognitive function. With evidence indicating that soluble forms of Aβ and τ work together, synapse dysfunction depended on the actions of both Aβ and τ. This fact came from the observation that removing endogenous τ in mutant APP-overexpressing mice by crossing them with a τ knockout line prevented Aβ-associated cognitive deficits and reduced the susceptibility to seizures induced by a γ-aminobutyric acid antagonist. ⁵¹ In cultured neurons, synthetic Aβ oligomers have been shown to induce neuritic degeneration in concert with τ hyperphosphorylation. ⁵² In addition, intracerebral injection of synthetic Aβ fibrils into mice transgenic for mutant human τ induced a 5-fold increase in the number of τ hyperphosphorylation in regions near the injection sites. ⁵³ Conversely, transgenic mice for both mutant human APP and τ undergo τ alterations that can be temporarily reversed by microinjecting anti-Aβ antibodies. ⁵⁴ Moreover, Aβ oligomers containing a truncated, N-terminally pyroglutaminylated form of Aβ implicated in AD pathogenesis were found to be highly toxic to cultured neurons in a τ-dependent manner. ⁵⁵ These studies support the pathogenic relationship between Aβ accumulation and τ-mediated neuronal alteration.

Expression of Aβ and τ-Proteins in the Skeletal Muscles

The pathologic and molecular substrate of people diagnosed with cognitive deficits and movement disturbance may not occur exclusively in the context of a brain region, but it may be expressed in another part of body such as muscle. In an observational cohort study of 900 community-based older persons without dementia followed for 3 to 6 years found that greater muscle strength is associated with a decreased risk of developing AD and MCI. ⁵⁶ However, the reason for the association between muscle strength and Alzheimer’s risk isn’t known yet. Microscopic evidence has been found that there is abnormal accumulation of Aβ and phosphorylated τ in skeletal muscle of patients with inclusion body myositis (IBM), and these muscle fibers also accumulate presenilin-1,39, which is considered to be the catalytic subunit of γ-secretase, suggesting that induced in the muscle weakness. ^57,58 Inclusion body myositis and AD share many pathohistological features including the buildup of aggregated proteins such as Aβ and τ. Interestingly, experimental studies in IBM animal models have found a marked elevation of Aβ ^57,59 and phosphorylated τ in skeletal muscle. ⁵⁷ Furthermore, other studies have demonstrated that ectopic expression of either APP or Aβ42 is sufficient to induce muscle cell death in both in vitro and in vivo animal models. ⁶⁰ In the nematode Caenorhabditis elegans, expression of Aβ42 results in protein aggregations within body wall muscles that result in paralysis and reduced longevity. ^61,62 On the other hand, τ was also demonstrated to be widely distributed in many tissues besides the nervous system, at relatively high levels in the heart, skeletal muscle, lung, kidney, and testis and at low levels in the adrenal gland, stomach, and liver. ⁶³ Other experimental studies demonstrate that τ knockout mice strain exhibit motor deficits and muscle weakness. ^64,65 Taken together, loss of physiological Aβ and τ function may contribute to the motor deficits observed in AD. However, a better understanding of this pathway in skeletal muscle and AD might provide a rationale for novel therapeutic strategies targeting pathogenic protein aggregation.

Comments

The pathogenic pathway of both Aβ and τ-protein in muscles as well as in the spinal cord gives rise to the consideration of mild movement disorders as a risk factor for future cognitive disorders. The early onset of appropriate changes in the spinal cord and muscles is an option for additional diagnostic procedures. Electromyographic examinations and studies of long pathways with somatosensory evoked potentials and magnetically evoked potentials could expand the diagnostic spectrum for the early diagnosis of both mild cognitive disorders and the risk of falls due to mild movement disorders. This would allow standard electrophysiological examination methods, such as P300 potential and electroencephalography, to be extended by noninvasive methods and possibly lead to an earlier diagnosis of cognitive and motor disorders. Further research in this area seems rewarding.

Conclusion

There is mounting evidence that motor function decline occurs early in the AD process, rather than being a feature exclusively related to end-stage AD pathology. Accurate clinical assessment of motor deficits might therefore represent a valuable marker for early diagnosis of AD. Together, these reviews suggest that motor and cognitive decline may share a common causation that may be exemplified by aggregation of Aβ and τ-protein and the pathogenic relationship between Aβ accumulation and τ-mediated motor and cognitive alteration. Key questions still remain open, such as the topographic distribution of Aβ and τ-protein in brain and other tissues of human body. The answers to these questions will probably enhance our understanding of the pathophysiological nature of Aβ and τ-protein and may also reveal new therapeutic targets and preventive strategies.