Bridging the Synaptic Gap: From Neuroplasticity to Cognitive Renewal
Amay Kashyap Deka
Delhi Public School, Guwahati Email: amaykashyapdeka@gmail.com
Abstract
Neurodegenerative diseases, particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD), have a debilitating impact on memory, perception, and overall cognitive function. They are among the leading causes of dementia, cognitive impairment, and memory decline, collectively affecting more than 50 million people worldwide. While neuron death is a known factor, a more immediate and significant cause of this decline is the loss of synaptic connections and the subsequent disruption of crucial neural networks. This paper aims to address three core areas in this respect:
The fundamental role of neuroplasticity in memory formation and cognitive recovery.
The direct link between synaptic degradation and memory loss.
The mechanisms of memory retrieval and the breakdown of long-term memory networks in neurodegeneration.
Furthermore, this paper will propose a multifaceted approach toward mitigating this problem, unifying pharmacological, technological, and lifestyle-based elements to form a comprehensive solution for cognitive renewal.
Background
This section aims to cover several key terminologies mentioned throughout the paper and provide a clearer picture of the underlying problem.
Neuroplasticity
The human brain is not a static organ; it is a dynamic system that constantly undergoes remodeling and rewiring based on various experiences, injuries, learning, and environmental stimuli. Neuroplasticity refers to the ability of the nervous system to change its structure and function, which involves forming, modifying, or removing neural connections. These connections can be weakened through a process known as long-term depression (LTD) or strengthened via long-term potentiation (LTP). LTP represents a persistent increase in synaptic strength triggered by coordinated cellular activity, forming the basis for memory encoding. Conversely, LTD involves a decrease in synaptic strength, which is crucial for pruning unnecessary or incorrect neural connections. A prime example of this dynamic capability is adult hippocampal neurogenesis, a process that occurs in the dentate gyrus and contributes to learning and memory throughout life.
Memory Systems
Human memory is not a single entity but comprises multiple systems. Episodic memory—the recollection of specific episodes or experiences—relies heavily on the hippocampus and the related medial temporal lobes. In contrast, long-term memory storage involves vast cortical networks, including the hippocampus, medial prefrontal cortex, posterior cingulate, and angular gyrus, which together form the default mode network (DMN). These networks are profoundly disrupted in disorders like AD and PD. The pathological hallmarks of AD, namely amyloid-β plaques and tau tangles, specifically target the hippocampus and compromise DMN connectivity, severely affecting the ability to form and retain memories.
Synaptic Loss
A core unifying factor in the progression of neurodegenerative diseases is the degree of synaptic loss. In both AD and PD, post-mortem studies reveal that the severity of memory loss correlates more strongly with the degree of synaptic loss than with the outright death of neurons. Soluble oligomeric forms of amyloid-β (Aβ) demonstrate a high degree of synaptotoxicity, actively inhibiting LTP and enhancing LTD. This toxic activity leads to the shrinkage of dendritic spines, effectively erasing the physical points of synaptic contact. For instance, researchers have found that in rodent models of PD, synaptic connections are disrupted even before memory deficits become apparent, indicating that the loss of synaptic potentiation may be the primary cause of cognitive decline.
Literature Review
Past Studies
Early work by researchers such as Bliss & Collingridge (1993) and Kandel (2001) established LTP and LTD as the foundational building blocks of neuroplasticity and memory. Seminal studies in neuropathology later linked dementia more directly to synapse loss than to overall neuron loss (Terry et al., 1991; Scheff & DeKosky, 1990). The devastating effect of Aβ oligomers on dendritic spine stability in AD was subsequently demonstrated in detail, confirming their role as primary synaptotoxic agents (Finnema et al., 2016; Toyonaga et al., 2019; Mecca et al., 2020). In the context of PD, it has been shown that dopamine gates plasticity, and its depletion degrades LTP and impairs certain memory-related behaviors. This damage is sometimes reversible with treatments like L-DOPA in specific cases (Calabresi/Picconi reviews).
Sources (Selected)
Bliss TVP & Collingridge GL (1993) Nature
Kandel ER (2001) Science
Terry RD et al. (1991) Annals of Neurology
Scheff SW & DeKosky ST (1990) Annals of Neurology
Selkoe DJ (2008) Behavioural Brain Research
Spires-Jones TL & Hyman BT (2014) Neuron
Finnema SJ et al. (2016) Science Translational Medicine
Toyonaga T et al. (2019) Journal of Nuclear Medicine
Mecca AP et al. (2020) Alzheimer's & Dementia
Greicius MD et al. (2004) PNAS
Buckner RL et al. (2008) Annals of the New York Academy of Sciences
Brier MR et al. (2012) Journal of Neuroscience
Eyler LT et al. (2019) Journal of Alzheimer's Disease
Lejko N et al. (2020) Journal of Alzheimer's Disease
Erickson KI et al. (2011) PNAS
Calabresi P & Picconi B (reviews on PD plasticity)
Synaptic Plasticity and Memory Loss in Parkinson’s and Alzheimer’s Disease
A commonality of both AD and PD pathologies is synaptic dysfunction, albeit through different molecular pathways. In AD, amyloid peptides and hyperphosphorylated tau proteins disrupt synaptic function from the outset. They bind to synaptic sites, disrupt calcium homeostasis, and activate destructive pathways involving enzymes like calcineurin and caspases. The end result is a significant loss of synaptic receptors, which correlates directly with cognitive and intellectual impairment, especially in the encoding of new memories. This has led many researchers to describe AD as a “synaptopathy”—a disease primarily of synapses—even though neuron death becomes significant in its later stages. Furthermore, misfolded tau proteins, which normally help stabilize the cytoskeleton in neurons, accumulate in dendrites and synapses, creating a physical barrier to synaptic transport. The only break in the clouds, perhaps, is the fact that synapses (in contrast to dead neurons) are potentially rescuable. Therapies like antibodies that clear amyloid peptides have shown promise, and immunotherapy is also being tested in this respect.
Fig: Tau and Oligomer pathology in AD (Frontiers)
In Parkinson’s disease, the initial pathology involves the degeneration of dopamine-producing neurons in the midbrain, which primarily affects motor skills. However, the hippocampus and the prefrontal cortex also receive dopaminergic projections that are vital for facilitating neuroplasticity and learning. In vivo studies on Parkinson's rodent models confirm this, showing that hippocampal LTP is reduced early in the disease's progression. As forementioned, L-DOPA, a precursor to dopamine, has shown results in restoring LTP and improving memory. The likely scenario is that dopamine exerts these effects by modulating NMDA receptor function, which is critical for excitatory neurotransmission. Alpha-synuclein, the protein implicated in PD, normally plays a role in neurotransmitter release. However, when misfolded, it can directly harm synapses. Investigations of PD patient brains show that alpha-synuclein aggregates are present even in the absence of neuron loss and can cause structural changes in the hippocampus. Furthermore, advanced PD can lead to Parkinson’s disease dementia (PDD), which is similar to the dementia caused by AD but includes the presence of Lewy bodies formed by alpha-synucleins. A potential solution in certain cases is the use of cholinesterase inhibitor drugs, which restore levels of acetylcholine, another key neurotransmitter.
Fig: In-vivo studies on Parkinson’s rodents (Journal of Neuroscience)
Although both diseases involve different molecules (Aβ/Tau proteins vs. α-synuclein), in both cases, the pathology results in weakened synaptic connections. Early detection of this synaptic decline could serve as a valuable diagnostic indicator. New imaging techniques, such as PET tracers that target synaptic proteins, represent a significant step in this direction.
Neural Networks and How They Can Be Restored
Networks are crucial for the preservation of memory because memory is not an isolated phenomenon involving a single brain element. Long-term storage and retrieval of memory involve a coordinated dance between the hippocampus (acting as an index or pointer) and the cortex (where memories are stored). Over time, memories become less dependent on the hippocampus and more reliant on these distributed cortical connections. Both AD and PD have devastating effects on this delicate interplay.
Network Disintegration in Alzheimer's Disease
In Alzheimer’s disease, the most significant display of network disintegration occurs within the default mode network (DMN), which is deeply involved in memory retrieval and self-referential thought. For example, one study found a moderate decrease in DMN functional connectivity between the posterior cingulate cortex and the right hippocampus, which correlated with cognitive decline and lower memory performance in AD patients. Amyloid plaques are also heavily concentrated in DMN regions, leading to extended dysconnectivity. Some researchers consider AD a "progressive disconnection syndrome," where the normal hippocampal-cortical dialogue fails. This is why, along with having trouble forming new memories, AD patients also lose old memories as these connections disintegrate. The Papez circuit (involving the fornix, mammillary bodies, hippocampus, cingulate cortex, and thalamus), which is vital for memory consolidation, is also affected by the atrophy of its various components in AD.
Fig: Affected connectivity in DMN (Aging US)
Network Disruption in Parkinson's Disease
In Parkinson’s disease, the early indications differ from those of AD, but the pathology begins to resemble AD in the later stages. Sub-cortical loops are heavily involved in the initial pathology. The basal-ganglia-thalamo-cortical circuits are disrupted by the dopamine loss mentioned previously, leading to both motor and memory retention issues. In a resting state, PD patients have shown reduced connectivity to the posterior DMN, similar to AD patients. However, a unique response to this is the emergence of compensatory network activity in PD. MRI images show the activation of other brain regions during memory tasks, representing an attempt by the brain to engage as many resources as possible to cope with the reduced capabilities of conventional memory circuits. As the disease progresses, this compensatory network becomes ineffective, and memory becomes increasingly difficult. Unlike AD, where the memory circuits themselves are the primary target, in PD, the neurotransmitter systems (dopamine, acetylcholine) are typically compromised first, and only then do the memory circuits degenerate.
Beyond structural integrity, the brain’s memory network relies on dynamic coordination—the precise timing of neural activity—which is also affected. For example, AD is associated with altered theta and gamma oscillations in the hippocampus. In PD, the normal pattern of cortical oscillations is disturbed by an excess of beta waves in the cortical-hippocampal network. The interconnection between various networks like the Papez circuit also suffers, leading to impairment in switching between different tasks and memories.
These findings reflect that therapeutic interventions for both AD and PD need to be network-informed. In AD, deep brain stimulation (DBS) of the fornix (a part of the Papez circuit) has been shown to improve memory retrieval by enhancing network activity. In PD, the effectiveness of DBS in increasing network connectivity is debated, but it is widely used to improve motor activity. Individuals with high cognitive reserves can often use their compensatory networks more effectively, delaying the onset of symptoms, which suggests that cognitive training and intellectual engagement can also be a powerful remedy.
Proposed Solutions
A one-sided solution will not solve this problem. To actually create an effective solution, the attack has to be done on multiple fronts – pharmacological therapies, gene, molecular techniques and enhancing neurotransmitter levels. As mentioned in the introduction, enhancing neuroplasticity in a large scale is the main goal of each of these solutions: -
Synapse Protective and Synapse-Loss Preventive Therapies
Synapse Loss, being a commonality in both AD and PD, in the initial as well as final stages correlates the best with the neuron death and memory loss. Therefore, measures have to be taken to protect existing synapses and promote formation of new ones.
In AD, anti-amyloid treatments such as antibiotics (Lecanemab) removed AD pathology and resulted in systems appearing much later. Neurotrophic factors like Brain derived neurotrophic factor (BDNF) upgrades synaptic density and cognitive performance. NGF (Nerve growth Factor) which is a family member of BDNF had been administered in a small trial of AD patients via gene therapy to the basal forebrain and showed trophic effects on neurons. Drugs such as ampakines prolong opening of the AMPAR and NMDAR modulators which enhance cognition. In the initial stages, these pharmaceuticals can play a role in delaying the onset of syndromes enhancing LTP and memory in a study in rodents.
In PD, since there is major dopamine loss, optimizing dopaminergic therapy is considered a major treatment. However, care must be taken as excess Dopaminergic treatment can disturb the balance of LTP/LTD. Preliminary studies on moelcules stabilizing dendritic spines have shown some prevention in amyloid plaque induced spine loss. Cholinesterase inhibitors (preventing formation of neurotransmitters) are already used in PDD and AD treatment. Low dose psychedelics like psilocybin could potentially improve synaptogenesis. However, clinical evidence is lacking, and several factors must be weighed.
Enhancing Neurogenesis and Brain Repair
Since the cortical-hippocampal connection is impaired early in AD, a multitude of approaches to boost neurogenesis will be useful. Strategies include lifestyle interventions like exercise, neurotransmitter-based approaches, transplanting stem cells, and administering neurotrophic factors like BDNF and NGF.
Gene Editing Approach
Technologies like CRISPR could play a role in enhancing plasticity. They could potentially be used to knock down genetic inhibitors of axonal growth or build cellular resistance to toxic proteins. Proof-of-concept studies have already used CRISPR to reduce amyloid production in cells.
Lifestyle Interventions
This class of solutions is by far the most benign and risk-free. It includes physical exercise, cognitive training, and dietary optimization. For example, a one-year exercise regimen in older women was shown to increase hippocampal volume by 2%. Another study provided convincing results that weight training improves memory performance by 15% in senior citizens.
Network Re-tuning
As mentioned earlier, Deep Brain Stimulation (DBS) has resulted in improved memory for both AD and PD patients. Non-invasive procedures like Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (t-DCS) have also been explored. Theta-burst TMS can improve LTP formation, while t-DCS applied to the prefrontal cortex has improved memory in AD patients.
Conclusion
Neurodegenerative diseases are fundamentally diseases of neuroplasticity. Toxic proteins such as amyloids, α-synuclein, and tau disrupt this vital process, leading to the disintegration of critical brain networks like the hippocampal-cortical system. However, the brain's capacity for change also offers a path toward recovery. A future, personalized approach that uses biomarkers to combine the right drugs, aerobic exercise, cognitive training, and targeted brain stimulation can help achieve this. By pairing these interventions with advanced imaging techniques, we can work to strengthen synapses, re-synchronize networks, and provide major relief and cognitive renewal to patients suffering from AD and PD.
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