Molecular Factors Mediating Neural Cell Plasticity Changes in Dementia Brain Diseases

Abstract

Neural plasticity-the ability to alter a neuronal response to environmental stimuli-is an important factor in learning and memory. Short-term synaptic plasticity and long-term synaptic plasticity, including long-term potentiation and long-term depression, are the most-characterized models of learning and memory at the molecular and cellular level. These processes are often disrupted by neurodegeneration-induced dementias. Alzheimer's disease (AD) accounts for 50% of cases of dementia. Vascular dementia (VaD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) constitute much of the remaining cases. While vascular lesions are the principal cause of VaD, neurodegenerative processes have been established as etiological agents of many dementia diseases. Chief among such processes is the deposition of pathological protein aggregates in vivo including β-amyloid deposition in AD, the formation of neurofibrillary tangles in AD and FTD, and the accumulation of Lewy bodies composed of α-synuclein aggregates in DLB and PDD. The main symptoms of dementia are cognitive decline and memory and learning impairment. Nonetheless, accurate diagnoses of neurodegenerative diseases can be difficult due to overlapping clinical symptoms and the diverse locations of cortical lesions. Still, new neuroimaging and molecular biomarkers have improved clinicians' diagnostic capabilities in the context of dementia and may lead to the development of more effective treatments. Both genetic and environmental factors may lead to the aggregation of pathological proteins and altered levels of cytokines, such that can trigger the formation of proinflammatory immunological phenotypes. This cascade of pathological changes provides fertile ground for the development of neural plasticity disorders and dementias. Available pharmacotherapy and disease-modifying therapies currently in clinical trials may modulate synaptic plasticity to mitigate the effects neuropathological changes have on cognitive function, memory, and learning. In this article, we review the neural plasticity changes seen in common neurodegenerative diseases from pathophysiological and clinical points of view and highlight potential molecular targets of disease-modifying therapies.

Figure 1

MRI (Gradient echo). 67F, presented with cognitive deficits which were first noticed by close relatives six years prior and initially thought to be due to severe depression. MMSE 18/30, ACER 58/100. MRI demonstrated extensive cerebral amyloid angiopathy.

Figure 2

84F, independent with activities of daily living, MMSE 30/30, ACER 84/100, but occasional odd behaviors noted by children in the recent weeks. Diagnosed with early frontotemporal dementia. (a) Brain MRI—moderate generalized enlargement of the ventricles and surface CSF spaces, particularly affecting the frontal lobes bilaterally. Mild presumed microangiopathic changes and tiny old scattered lacunes. No features of remote microhemorrhages. (b) Brain SPECT—decreased activity is seen predominantly at both frontal lobes. There is also involvement of the anterior and mesial temporal lobes.

Figure 3

Changes in synaptic plasticity and the development of dementia in common dementia diseases. AD: Alzheimer's disease; FTD: frontotemporal dementia; VaD: vascular dementia; DLB: dementia with Lewy bodies; PDD: Parkinson's disease (PD) dementia; Aβ: β-amyloid; NFTs: neurofibrillary tangles; APP: amyloid precursor protein; LB: Lewy bodies; ASN: alpha-synuclein; ApoE4: apolipoprotein E.

Figure 4

Changes in the level of neurotrophins and synaptic plasticity in the development of dementia diseases. AD: Alzheimer's disease; FTD: frontotemporal dementia; VaD: vascular dementia; DLB: dementia with Lewy bodies; PDD: Parkinson's disease (PD) dementia; BDNF: brain-derived neurotrophic factor; NGF: nerve growth factor; GDNF: glial-cell-derived neurotrophic factor; NE: norepinephrine; E: epinephrine; DA: dopamine; 5-HT: serotonin; ACh: acetylcholine; IL-1α: interleukin-1alpha; IL-1β: interleukin-1beta; IL-6: interleukin 6; TNF-α: tumor necrosis factor-alpha.