Biomarkers of Activity-Dependent Plasticity and Persistent Enhancement of Synaptic Transmission in Alzheimer Disease: A Review of the Current Status

Abstract

Alzheimer disease (AD) is a chronic and heterogeneous neurodegenerative disorder characterized by complex pathological processes involving neuroinflammation, neurodegeneration, and synaptic dysfunction. Understanding the exact neurobiological mechanisms underlying AD pathology may help to provide a biomarker for early diagnosis or at least for assessment of vulnerability to dementia development. Neural plasticity is defined as a capability of the brain to respond to alterations including aging, injury, or learning, with a crucial role of synaptic elements. Long-term potentiation (LTP) and long-term depression (LTD) are important in regulating synaptic connections between neural cells in functional plasticity. Synaptic loss and impairment of the brain's plasticity in AD leads to cognitive impairment, and one of important roles of synaptic biomarkers is monitoring synaptic dysfunction, response to treatment, and predicting future development of AD. Synaptic biomarkers are undoubtedly very promising in developing novel approach to AD treatment and control, especially in the era of aging of societies, which is one of the most common risk factor of AD. Implementing a widespread measurement of synaptic biomarkers of AD will probably be crucial in early diagnosis of AD, early therapeutic intervention, monitoring progression of the disease, or response to treatment. One of the most important challenges is finding a biomarker whose blood concentration correlates with its level in the central nervous system (CNS). This review aims to present the current status of biomarkers of activity-dependent plasticity and persistent enhancement of synaptic transmission in Alzheimer disease.

Perfusion-weighted software written in Python for DSC-MRI analysis

“…Recently, cerebrovascular dysfunction has emerged as an early manifestation of Alzheimer's disease with a direct impact on the evolution and clinical expression of dementia. It has been shown that mice expressing mutated tau exhibit a selective suppression of neural activity-induced CBF increases that precedes tau pathology and cognitive impairment (Warpechowski et al, 2023 ). Regarding stroke, these parametric maps help to diagnose and predict the final cerebral ischemic stroke volume identifying core and penumbra regions (Demeestere et al, 2020 ).…”

“…It is possible to acquire functional information about perfusion-related parameters such as cerebral blood flow (CBF), mean transit time (MTT), and cerebral blood volume (CBV) (Keston et al, 2003 ; Østergaard, 2004 ). The accurate quantification of these parameters has several clinical applications, including the identification and evaluation of ischemic stroke prior to treatment (Calamante et al, 2002 ; Callewaert et al, 2021 ), the description of lesions associated with multiple sclerosis (Haselhorst et al, 2000 ; D'haeseleer et al, 2015 ), the diagnosis of tumors (Stadlbauer et al, 2015 ; Choi et al, 2016 ), or as trackers of Alzheimer's disease progression (Lacalle-Aurioles et al, 2014 ; Warpechowski et al, 2023 ).…”

Therapeutic Strategies Aimed at Improving Neuroplasticity in Alzheimer Disease

“…CSF biomarkers of plasticity include: neurogranin, a postsynaptic protein involved in synaptic plasticity and LTP [37], whose levels are usually higher in AD patients [38]; synaptosome-associated protein-25 (SNAP-25), which participates in the control of synaptic plasticity [39] and is usually higher in AD patients [40]; brain-derived neurotrophic factor (BDNF), essential for memory formation and structural plasticity [41] Measuring neuroplasticity in human subjects is obviously precluded by ethical and methodological considerations, calling for the use of proxy measures. Thus, measuring neuroplasticity was for many years restricted to the use of neuropsychological tests [30], such as the Battery of Learning Potential for Assessing Dementia [31] or the re-adapted Auditory Verbal Learning Test [32], and indirect biomarkers in serum and cerebrospinal fluid (CSF) [33][34][35][36]. CSF biomarkers of plasticity include: neurogranin, a postsynaptic protein involved in synaptic plasticity and LTP [37], whose levels are usually higher in AD patients [38]; synaptosome-associated protein-25 (SNAP-25), which participates in the control of synaptic plasticity [39] and is usually higher in AD patients [40]; brain-derived neurotrophic factor (BDNF), essential for memory formation and structural plasticity [41] and which is lower in MCI and AD patients [42,43]; and vascular endothelial growth factor (VEGF), a protein involved in the growth of blood vessels and delivery of glucose that has a role in enhancing neurogenesis and synaptic plasticity [33] (see Table 1).…”

The role of glycogen synthase kinase 3 beta in neurodegenerative diseases

“…Synaptic dysfunction is an early sign of AD ( Tönnies and Trushina, 2017 ). Long-term potentiation (LTP) and long-term depression (LTD) are crucial for regulating synaptic connections between neurons ( Warpechowski et al, 2023 ). LTP refers to the long-lasting increase in synaptic strength, while LTD is defined as the opposing process.…”