Notes for the latest paper:
- "However, problems with multiple clinical trials of amyloid-targeting therapeutics, including an effective removal of neurotoxic Aß species, and licensed AD therapeutic drugs are their lack of effectiveness in targeting the pathophysiological core underlying the dementia: functional deficits/loss of synapses and neurons beyond the brain’s ability to repair. Synapses permit a neuron to pass a signal, chemical or electric, to another cell and are adaptive in operation and structure according to functional demands. Both acquisition of memory and its consolidation/reconsolidation involve restructuring of synapses and their operations [9]. For all the unsettled issues in AD, one finding is clear: the synaptic deficit/loss, revealed among many other pathologies, is highly correlated with the levels of dementia in AD patients [10–12] (Box 1). Within 2–4 years of AD onset, brain biopsies are reported to have a decrease in the number of synapses by 25–30% in the frontal and temporal cortexes [13], most severe (by 44–55%) in the hippocampus [11,14], both in the degenerated and surviving neurons (about 38% loss [12,13]).
- "Mammalian brains operate on an efficiency principal of keeping the number of synapses modest for a particular function, since signal transfer through synapses is rather expensive in energy cost [19]. Powered through plasticity, the brain, however, can remodel its structure and operation of synapses/network for new challenges. The downside of this efficiency, the lack of abundance in neural connections, is its vulnerability to injury/damage, especially when this remodeling/regeneration ability is compromised."
- "Mammalian brains have a certain capacity to regenerate/remodel synapses/neural networks when facing injury, disorders, and cognitive challenges. Cognitive impairment becomes evident only when injury/damage/cognitive demands reach a threshold by which the brain can no longer initiate and sustain the required responses."
- "Memory impairment and dementia are the consequences of synaptic/neuronal deficits. The intrinsic neuro-regeneration capacity in the mammalian brain has been shown to be very limited, even after eliminating multiple known inhibitory signals [47]. In the adult mouse brain, most axons cannot regenerate sufficiently, even with precise laser-mediated lesions that produce minor scarring [48]. This low endogenous capacity for neuro-regeneration in mammalian brains does not mean, however, that this capacity cannot be enhanced to achieve dramatic outcomes. Spines are highly dynamic and capable of remodeling and restoring their original structure, location, and function [49], when triggered with appropriate therapeutics, such as neurotrophic activators (see below)."
- "With a focus on reversing synaptic and neuronal loss in AD, we have developed a therapeutic strategy that has shown a neurorestorative potential (i.e., to restore lost synapses in AD brains in preclinical studies) [9,95], as well as the concomitant potential to prevent apoptosis [9,96–98], reduce Aß oligomers, lower hyperphosphorylated tau [9,97–100], mRNA stabilization of growth factor mRNAs, and reduce oxidative stress [101]. Activators of PKCe (Figure 2) with bryostatin-1, a relatively selective and powerful PKCe activator with clinical safety profile at appropriate doses [102], and DCP-LA (Figure 3) have been shown to increase synaptic numbers via synaptic growth factors [103,104]. Bryostatin-1, a macrocyclic lactone, enhances BDNF expression/secretion and synaptic remodeling/synaptogenesis in the brain and produces several other anti-AD effects, such as antiapoptosis, anti-inflammation, antiamyloidosis, antitauopathy, and antioxidant, at therapeutic doses [10,105]."
- "Evidence supports the notion that cognitive deficits occur only when synapses/neural network cannot be appropriately maintained through neuronal/synaptic repair and synaptogenesis/neuro-regeneration to meet cognitive demands, indicating that synaptic deficiency should be the focused therapeutic target. The synaptic deficiency hypothesis (Figure 1), consistent with enormous evidence that an early failed maintenance in synaptic integrity triggers neurodegeneration in the brain and cognitive decline, does not rule out the pathological contribution of neurotoxic Aß and tauopathy to synaptic/cognitive deficits in AD and potential therapeutic benefits of anti-Aß and antitauopathy."
- "Accumulating evidence, to date, suggests that structural and functional deficits of synapses are at the core of the underlying pathophysiology in AD (see Outstanding Questions). In clinical trials, AD therapeutics that target synaptic loss and dysfunction (i.e., to slow, halt, or reverse progression of the disorders at the level of synapses), via synaptogenic molecular cascades such as the PKC-BDNF signaling pathway, show promising results [105]. This differs from the failure of 300–400 AD drug candidates in recent years [116]. The key to effective neurotrophic therapy in AD appears to require a sustained and appropriate PKC-BDNF activity in the brain, guiding against the aging/disease-related neurodegenerative process. A too-high level of PKC-BDNF activity can also be neurotoxic [117,118]. Overcoming the self-repair limitation in the mammalian brain would transform how AD patients, and others with memory disorders, are treated clinically."
