Alzheimer’s Therapeutic Development: Shifting Neurodegeneration to Neuro-regeneration

Abstract

Alzheimer’s disease (AD), like other AD-related dementias, is characterized by impaired/lost neuronal structures and functions due to a long progression of neurodegeneration. Derailed endogenous signal pathways and disease processes play critical roles in neurodegeneration and are pharmacological targets in inducing balance towards neuro-regeneration. Switching/shifting the brain status from neurodegeneration to neuro-regeneration pharmacologically is emerging as a new therapeutic concept, not only achievable but also essential in effective therapy for AD. The results of the pharmacological-induced shift from neurodegeneration to neuro-regeneration are two-folds: 1) arresting cognitive deterioration (and towards cognitive recovery) in established AD; and 2) preventing neurodegeneration through building-up cognitive resilience in preclinical and probable AD. These new developments in AD pharmacology and relevant clinical trials are discussed.

Alzheimer Disease: in Need of Therapeutics with Clinically Meaningful Efficacy in Cognitive Improvement

Alzheimer’s Disease (AD), the leading neurodegenerative disorder, has emerged among the most dreaded diseases [1, 2] due to a lack of effective therapies. In the US alone, AD cases are currently numbered at 6.2 million and anticipated to grow to 12.7 million in 2050 [3]. Four of the six FDA approved drugs (donepezil, galantamine, rivastigmine, and memantine) provide only symptomatic short-term benefit for the mild AD cases. Aducanumab and Lecanemab, the most recently approved monoclonal antibodies, remain controversial [4], for not showing a clear improvement in cognition [5], or not stopping cognitive decline in AD patients [6]. In addition, Aducanumab and Lecanemab have significant safety issues. Anti-Aβ therapies compromise long-term brain health by accelerating brain atrophy [7], an impact that seems opposite to the ultimate therapeutic goal, halting/reversing the underlying neurodegenerative progression. It remains to be seen whether their additional confirmatory trials would resolve the issues of safety and long-term efficacy.

The goals of AD therapeutic development are to find drugs that produce clinical efficacy in AD cognitive improvement. The non-existing and limited cognitive benefit of the newly approved Aβ antibodies calls for new lines of therapeutic development with clinical meaningful benefit. New evidence is emerging that shifting neurodegeneration to neuro-regeneration pharmacologically may represent a more effective therapeutic strategy against AD [8–10]. Pharmacological shift of the balance from neurodegeneration to neuro-regeneration may reverse/halt cognitive deterioration in established AD and greatly enhance cognitive resilience in preclinical AD against AD progression. We discuss these new developments and clinical trials to guide future research and AD drug development.

AD, a Cognitive Disorder of Progressive Neurodegeneration and Neurotrophic Insufficiency

The majority of AD cases are sporadic, with only <5% cases that may be directly linked to gene mutations. The percentage is higher when other gene/variants, such as APOE4, are considered [11]. The word “dementia” defines a condition of progressive loss of cognitive functions, i.e., deterioration of memory, language, and other cognitive abilities. Neurodegeneration, “degeneration” of neurons, is a progressive loss of neuronal structures, from synapses to neural atrophy and death. It begins as a disease of dystrophic neurites, synaptic dysfunction, and loss of synapses, especially in the limbic and neocortical cortices.

AD, the leading neurodegenerative disorder, is characterized by pathological features: extracellular neuritic Aβ plaques (NPs), intracellular tangles of hyperphosphorylated tau (neurofibrillary tangles [NFTs], tauopathy), and relentlessly progressive synaptic/neuronal degeneration [12].

Neurodegeneration and cognitive deficits are a common feature of reduced activity/levels of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF). Early studies of in situ hybridization from hippocampal samples of AD donors revealed decreased BDNF signal in the hippocampus and associative cortices, but not NGF or neurotrophin 3 (NT-3) [13, 14]. BDNF activity is negatively correlated to neurodegenerative disorders. Down regulation of BDNF and its cognate neurotrophic receptor, tropomysin receptor kinase B (TrkB), contributes to AD pathology, such as amyloidosis and tauopathy [15]. Attenuating BDNF/TrkB signaling deficits has been suggested to abrogate NPs and/or NFTs [15]. Interestingly, cerebrospinal fluid from young mice was found to restore cognition in aged mice through fibroblast growth factor 17 [16]. It is well known that under conditions of insufficient neurotrophic activity, a neuron may choose the programmed cell death [17, 18] in order to increase their neighboring neurons’ chance to survive. Zebrafish has strong regenerative capacity, an ability sufficiently counteracting neurodegeneration and highly dependent on neurotrophins [19]. In Adult zebrafish AD models, suppression of neural stem cell proliferation by serotonin is mediated through down-regulation of BDNF expression [20]. It has been reported that mimetics of exercise through enhancing BDNF activity and adult hippocampal neurogenesis improve cognition in mouse AD models [21]. The evidence shows therapeutic potential of BDNF and NGF signaling [22]. Increases in neurotrophic factors thus favor neuronal survival and functions and shift balance from neurodegeneration to neuro-regeneration in adult brains.

Vulnerability of Cognitive/Synaptic Functions to Neurodegeneration

In cognitive tasks of mammals, a neuron does not operate as an independent coding unit [23, 24]. The special selection of individual hippocampal CA1 neurons, for instance, requires local circuit amplification for effective multi-neuronal representation [23]. Synapses, the sites where functional connection and information transmission occur among neurons, however, are structurally and operationally unstable and dynamic.

Synaptic and neuronal loss is a defining feature of neurodegenerative diseases. The brain structures, synapses and neurons are vulnerable to a variety of injuries, disorders, genetic/environmental factors, infection [25, 26], and aging [27]. Several factors have been identified to associate with brains’ shift to neurodegeneration from neuro-regeneration: insufficient expression/levels of neurotrophins, an inflammatory cytokine profile, a lack of critical synaptic/network structures/operations and the ability to maintain synaptic/network structures/operations. Synaptic dysfunction/degeneration, starting long before the loss of memory and accelerating as diseases progress, precedes axonal degeneration and neuronal death. Cognitive deficits occur only when synapses/neural networks cannot be appropriately maintained to meet the cognitive demands in their responding pattern and local signal processing/amplification [23].

Neuro-regeneration Requires Sufficient Neurotrophic Activity

Neuro-regeneration is the regrowth or repair of neural structure and connection, with a consequence of cognitive recovery from neurodegeneration. The brain processes of neurodegeneration and neuro-regeneration, lying within its biology, is dynamic in both human and animal models. “Shifting the balance from neurodegeneration to neuro-regeneration,” the core to reverse cognitive decline, depends on regenerating normal dendritic structures and synapses.

It is thus important to define pathological factors/mechanisms that “switch-off” the endogenous neuro-regeneration. Preservation of synaptic integrity from loss and neurodegeneration does not necessarily require removing Aβ, including soluble and insoluble Aβ [28]. Because of their hydrolytic properties, Aβ peptides (especially Aβ1−42) oligomerize rapidly, forming various forms of oligomers, some of which are considered neurotoxic. A recent positron emission tomography imaging study in AD cases shows that cognitively healthy brains have similar amounts of dissolvable, non-fibrillar amyloid protein as brains of AD patients and that very few cases of dementia occur with amyloid plaques, or masses of aggregated Aβ protein [29]. Anti-β antibodies appear accelerating brain atrophy [7]. These new observations [7, 28, 29] suggest that brain amyloidosis and tauopathy may not be the core underlying cause responsible for impaired neuro-regeneration in AD.

Neuro-regeneration requires the activities of neurotrophins. BDNF, for instance, is widely expressed in the brain structures critical for cognition [30]. Its expression and activity are reduced in preclinical and very early stage of cognitive impairment in AD [31]. Boosting endogenous regenerative signaling is beneficial in restoring the balance [32, 33] and/or achieving a new one unless the signal systems are overdriven. Brain BDNF expression is sensitive to lifestyle changes, such as mental and physical exercise [21] and meditation, which reduce inflammation and promote neurotrophic activities [34]. However, improved synaptic/neuronal regeneration through life-style changes requires lasting time and effort and is mild in strength, often insufficient to maintain appropriate neuro-regeneration. Shifting from neurodegeneration to neuro-regeneration pharmacologically ([32, 33] and see below), on the other hand, is more powerful and represents a new strategy in the fight against AD.

Pharmacologically Shifting Neurodegeneration to Neuro-regeneration for established AD

Successful AD therapy relies heavily on its therapeutic strategy, i.e., what to target pharmacologically. Pharmacologically shifting the brain status from neurodegeneration to neuro-regeneration of the very neural structures that cognitive functions rely on is not only achievable but also essential in an effective AD therapy. Several factors emerged recently as potential therapeutic targets in sifting/switching the balance between neurodegeneration and neuro-regeneration.

Amyloidosis and tauopathy

The critical contribution of amyloidosis and tauopathy to initiation and acceleration of cognitive decline and dementia in AD is supported by numerous studies [35–39]. On the other hand, the core role of amyloidosis and tauopathy in AD pathology has been challenged by others who report that prevention of the neuro-connections in the brains from breakdown, without removing Aβ and/or tauopathy, is sufficient in preventing dendritic spine loss, hippocampal neurodegeneration, and deficits in cognition [28]. The latter is consistent with the observations that Aβ and NFTs not only occur in dementia patients, but also in the brains of cognitively normal elderly. DRNC (dementia-related neurologic changes), such as high levels of β-amyloid and/or tauopathy in the brains, hippocampal sclerosis, microvascular lesions, or APOE genotype, alone may be insufficient to cause clinical dementia in a large number of individuals [40, 41]. On the other hand, no studies show that therapeutic efficacy for AD cognition can be achieved without improving neuro-regeneration and synaptic function. It remains to be defined whether elimination of amyloidosis and tauopathy can shift neurodegeneration to neuro-regeneration.

RNA Editing

Reduced RNA editing at the Q/R site of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA2 subunit increases AMPA receptor calcium permeability, leading to dendritic spine loss, neurodegeneration, and cognitive impairment [28, 42]. Eliminating unedited GluA2(Q) expression in AD mice prevents spine loss and hippocampal CA1 neurodegeneration and improves cognition [28]. Thus, RNA editing at the Q/R site of AMPA receptor GluA2 subunit may represent a switch regulating dendritic spine and neurodegeneration [28]. However, there is no direct in vivo evidence that RNA editing deficits are linked to human AD.

Neurotrophic factors

A number of other factors have been identified potentially to associate with the balance shift. Four of the factors are at the core of neurodegeneration vs. neuro-regeneration: 1). A sufficient vs. deficit in expression/levels of neurotrophins; 2). An inflammatory vs. anti-inflammatory cytokine profile and cell infiltration [36]; 3). The existence vs. lack of critical synaptic/network structures/operations, such as spine density to initiate local circuit amplification in cognitive tasks [23]; and 4). The ability to maintain synaptic/network structures/operations through neuro-regeneration, even in the presence of severe adversities.

1). BDNF – PKCε activators

The synaptic dysfunction and loss are largely mediated by deficits in BDNF expression and deficits in the kinase Cε (PKCε) signal pathway and are responsible for cognitive deficits long before or even in the absence of neuronal loss. PKCε also interacts with mRNA-binding proteins such as HuD [43] to stabilize and prolong the mRNA of a number of synaptic growth factors, including BDNF.

BDNF is one of the genes that are positively associated with maintained high cognitive function late-in-life in AD [44]. A single-nucleotide polymorphism in BDNF (BDNF_Val66Met) was found to be associated with worsened cognitive decline. Human loss of function BDNF/TrkB variants impairs hippocampal synaptogenesis and cognition [45]. Cultured hippocampal and cortical neurons treated with 1–100 ng/ml BDNF are relatively resistant to being damaged or killed by insults relevant to acute/chronic neurodegeneration: neuro-excitotoxins [46], glucose/oxygen deprivation, oxidants, mitochondrial toxins, and Aβ. Efforts have been devoted to in vivo BDNF-based treatments: BDNF administration, viral induction of BDNF expression, enhancing BDNF activity/levels through signal pathways, and stem-cell-based therapies. The late stages of AD are associated with a significant loss of neurons. BDNF plays an essential role in neurogenesis [47], [10, 48, 49], and neuron-replacing treatment with neural stem cells [50]. Stem-cell-based therapies, however, face several hindrances in development, including ethical controversy, immune rejection, final commitments, and limited functional integration.

Neurotrophins are large molecules with a short half-life of 30 min or less, inefficient in tissue diffusion, and cannot cross the blood brain barrier. Poor pharmacokinetics may determine unsuccessful outcomes in some earlier clinical trials with oral BDNF supplementation or intrathecal BDNF. A recent phase II clinical trial with a BDNF enhancer, bryostatin-1, reveals successfully halting AD cognitive progression in a subset advanced AD patients with MMSE II 10–14 [10].

2). Other neurotrophin-enhancers

Other compounds have also been reported to express neurotrophin-enhancing profiles and a few are currently in clinical trials (table 1). Some candidates failed due to lack of efficacy, while others showed promising potential or remained to be reported. AD clinical trials have some major issues in trial design. Targeting an active endogenous signaling pathway faces additional challenges, such as achieving optimal benefits without overdriving the biological system. BDNF mimetics, such as 7,8-dihydrodxyflavone (DHF) and bis-(N-monosuccinyl-L-seryl-L-Lysine (GSB-106), which can bind and initiate TrkB signaling pathway, have shown some promising benefits in AD models [51]. Approaches to increase BDNF promote cognitive/synaptic regeneration in AD mice as well as in AD patients, involving several critical molecular signal pathways (Figure 1 [10,32]), such as PKCε-BDNF, Mef2 (myocyte enhancer factor 2) family of transcription factors, phospholipase A2 group IVE (PLA2G4E; [52]), triggering receptor expressed on myeloid cells 2 (TREM2; [53–55]), Kdm6a, (a gene on the X chromosome, providing instructions for making an enzyme called lysine-specific demethylase 6A, which functions as a histone demethylase), and PI3Kα (Phosphoinositide 3-kinases α; [56]). PI3Kα is an important effector of growth factor signaling. UCL-TRO-1938, an allosteric PI3Kα activator, was found to enhance nerve regeneration in rodent models [56], consistent with the evidence that PI3K inhibition impairs regenerative effects of growth factors from neuroprotection/regeneration [57]. NNI-362 promotes neuron regeneration-associative reversal of AD-related cognitive deficits [58]. Fosgonimeton, a positive modulator of hepatocyte growth factor/tyrosine kinase receptor (HGF/MET) has also been developed as an agent that promotes neuro-regeneration ([59] Table 1). Promoting synaptic functions/regeneration through BDNF with PKCε has yielded great results [10, 33]. These new findings of the anti-inflammation and molecular regulation of synaptic formation and function in fully differentiated brain networks provide an important new set of pharmacologic targets to recover synaptic and cognitive functions.

Table 1.

Agents (with neurotrophin-promoting profiles) currently/recently in Phae II/III clinical trials of Alzheimer’s disease drug development.

Drug candidates	Clinical Trials (Phases)	Therapeutic Targets	Trial Outcomes	Reference
Fosgonimeton (ATH-1017)	NCT04488419 (2/3)	Promoting neuronal survival and synaptic plasticity through Hepatocyte growth factor	Phase 2 trial did not achieve its primary endpoint and secondary measures	[59]
Metformin	NCT04098666 (2/3)	Promoting neurotrophic activity (BDNF) and neurogenesis	Ongoing trial and no results yet	[60]
Bryostatin-1	NCT02925650 (2)	Promoting neurotrophic activity (BDNF) and reducing amyloidosis and Tauopathy	The trial did not achieve its primary endpoint but arrested cognitive decline in MMSE II 10–14 (the secondary endpoints)	[10, 48]
NNI-362	NCT04074837 (1a)	Promoting neurogenesis through allosterically stimulation of pleiotropic kinase, p70S6 kinase	Safe and reduced blood levels of an Alzheimer’s biomarker in a Phase 1a trial of the therapy in healthy, older adults	[58]
Caffeine	NCT04570085 (3)	Promoting cognition and inhibiting adenosine receptors	Ongoing trial and no results yet	[61]
Edonergic (T-817MA)	NCT04191486 (2)	Neurotrophic, activating sigma-1 receptor	Ongoing trial and no results yet	[62]

Figure 1.

The synaptic PKC–BDNF signaling pathway. Many signaling molecules are involved: such as mitogen-activated protein kinase (MAPK) kinase (MEK), MAPK, Raf, extracellular signal-regulated kinase (ERK) 1/2, and growth associated protein 43 (GAP-43), tyrosine kinase B (TrkB), phosphatidylinositol 3-kinase (P.3K), phospholipase C (PLC), and diacylglycerol (DAG). These factors are also potential therapeutic targets in AD drug development.

3). Telomeres

Interesting phenomena in cellular aging are the telomeres, whose length is shortened since the outer part cannot be replicated with each cell division or under un-replicable conditions. Though not always consistently [63], shortening leucocyte telomere length is associated with lower volumes of total brain and hippocampus and a higher risk of dementia and AD [64], and predicts AD incidence [65]. Responsible for the replication of telomere DNA is the enzyme telomerase. Telomerase synthesizes telomere repeats through its catalytic telomerase reverse transcriptase subunit (TERT). Evidence has been presented that BDNF and telomere length are associated with neural survival and cognitive function [64]. Telomerase activity mediates the neuroprotective effects of BDNF by inhibiting apoptosis in rodent models [66]. BDNF-dependent telomerase activity and TERT promote neuronal survival in developing hippocampal neurons [66]. TERT also upregulates BDNF and other neurotrophic factors in the hippocampus. It remains to be studied whether telomere pharmacology can bring cognitive benefit through shifting brain balance of neurodegeneration to neuro-regeneration.

Pharmacologically Enhancing Cognitive Resilience for Preclinical AD

In addition to its potential as therapeutic drug for AD, shifting/switching the balance from neurodegeneration to neuro-regeneration pharmacologically may effectively prevent cognitive deterioration in preclinical AD individuals. The underlying mechanisms are endogenous capacities of the so-called “Cognitive Resilience” [18, 57], which has been observed in up-to one-third of elderly (over 80) and 50% of the oldest-old [67, 68] cognition-normal individuals, despite severe AD pathologies in their brains [24, 69, 70] (Figure 2). The existence of pathologies in these patients was confirmed with cerebrospinal fluid AD biomarker, amyloid- or tau-specific imaging techniques, or autopsy, and advanced age. For instance, carriers of the PSEN1-E280A mutation consistently show minimal cognitive impairment by the age of 44 and dementia by 49, with rare exceptions. Some of the PSEN1-E280A mutation carriers, however, remained cognitively intact until 67 years of age [24] or nearly 30 years after the expected age clinical onset despite extremely elevated amyloidosis, suggesting a role of RELN signaling in cognitive resilience against AD [24].

Figure 2.

The concept of cognitive/synaptic resilience and pharmacology. Cognitive resilience, an individual’s overall cognitive resources at a given point in time, is about individual differences in how tasks are performed that may allow some people to be more resilient than others to cognitive adversities. It is calculated as the difference between the observed and the expected levels of cognition, after accounting for the pathological severity at the age in a linear regression method [58]. Cognitive/synaptic resilience is responsible for the preservation of memory and other cognitive functions, which are impaired by damaging neuropathology in memory disorders or reduced in aging. Potential influences are listed (Top): Intellectual enrichment, Physical activity, Sex-related factors, Diets, and Genetic factors? (not well defined) and impact on the resilience (Middle; through its four major components either negatively (−) or positively (+). The outcome is either DAD, a gradual cognitive decline and dementia years before death (Bottom left) or NDAD, a maintained cognitive health and cognitive normal at the time of death (Years before death at 0; Bottom right), although similar age-related accumulation of DRNC occurs in DAD and NDAD. Resilience pharmacology enhances the endogenous synaptic/cognitive mechanisms, so that cognitive function is maintained during an individual’s lifespan, despite similar levels of DRNC.

Resilient individuals have better maintained functional connectivity of neurons, exhibiting good preservation of the numbers of neurons/synapses throughout their lifespan, higher levels of neurotrophins and anti-inflammatory cytokines, and lower levels of chemokines associated with microglial recruitment and activation - virtually the same profiles separating neuro-regeneration from neurodegeneration. The behavioral correlates of cognitive resilience include greater education [38, 71], IQ, exercise [72], and gender (female). Estrogen reduces AD risk [73]. Reduction in estrogen level in menopausal females, however, puts them at a higher risk of cognitive decline and AD [74], probably due to different biobehavioral responses between males and females to stress [75]. The same phenomenon is also observed in rat models [76], and as well as AD mice. Although most AD models have been created using genetic manipulations of the genes leading to Aβ or tau pathology or injecting neurotoxic forms of these proteins into the brain, whether a particular mouse exhibits cognitive impairment is not significantly associated with amyloid plaque density, levels of tauopathy, or markers of glial activation.

Cognitive resilience is centered on synaptic resilience. The core feature of synaptic resilience in cognitive resilience is supported by several critical observations. First, cognitive resilience requires timely organized information processes through sets of neural networks and synapses, which play an essential role in cognition. The timely organized information processes involve dynamic changes of structure and chemistry of existing synapses, formation of new synapses, and elimination of old ones. Second, synaptic failure is an immediate and direct cause of cognitive impairment/dementia in animals and AD. Synapse dysfunction and loss occur at early stages of AD [39] and is also progressive in extent and severity during the years of AD progression, whilst cell death occurs at later stages [39]. It has been known for quite a while that only the loss of synapses appears to be an absolute predictor of dementia [77–79]. The link between greater loss of dendritic spines and lower cognitive function [77, 78] suggests that the progressive loss of dendritic spines in neurodegeneration underlies pathogenesis of dementia in AD and the diminishment of cognitive resilience. Third, NDAD (non-demented with AD pathology versus DAD [demented with AD pathology]) individuals show no or little synapse loss, when facing various pathologies including amyloidosis, tauopathy, inflammation, and oxidants. Fourth, cognition is directly affected by dynamic changes of adverse factors [36], and as well as signaling molecules that confer synapses with resilience.

It is not surprising that synapses play a central role in neuro-regeneration and cognitive resilience. Excitatory synapses mostly occur on dendritic spines in the brain. Dendritic spines are classified in their three-dimensional morphology in size and shape as thin, stubby, mushroom spines, while dendritic filopodia, thin, mostly needle-like, membrane protrusions, are considered precursors to spines [32]. Each spine has a neck and a head and the latter contains molecules critical for synaptic signaling. Morphology and density of spines are highly dynamic and are closely linked to synaptic activity and strength [80]. Cognitive decline/impairment is believed to be driven by subtle changes in dendritic spine density and morphology, while evidence of age-related neuronal loss is lacking, at least at early AD stages [81]. Resilient individuals maintain their dendritic spines: more thin and mushroom spines [82], despite the existence of DRNC.

What factors are then responsible for spine preservation? Evidence points to the same factors/signaling pathways important in shifting balance between neurodegeneration and neuro-regeneration.

BDNF

Among the several neurotrophins (BDNF, NGFs, NT-3, and neurotrophin 4 [NT-4]) in mammals, BDNF is unique in its synatogenic and activity-dependent activation. It promotes dendritic growth and spine morphogenesis and plays critical roles in synaptic functions/integrity and cognition. Development of resilience and exposure to an enriched environment are related to increased levels of BDNF. BDNF binds the tropomyosin kinase receptor B (TrkB) to trigger different signaling pathways, such as ERK1/2 and PI3K-mTOR, to induce dendritic growth and synaptogenesis (Figure 2). In addition to its trophic action on neurons, BDNF/TrkB signaling plays an important role in organizing cytoarchitecture and connectivity in the cortices [82]. Less well studied are the importance in synaptic/cognitive resilience of signaling through p75^NTR receptor, pro forms of BDNF, and NGF.

Triggering receptor expressed on myeloid cells 2 (TREM2)

TREM2, a cell surface receptor expressed on microglia in the brain, is required in physiological synapse elimination and brain connectivity. Microglia are innate immune cells of the brain, playing important roles in neurodevelopment, synaptic function regulation, and immune responses, functioning as resident macrophages of the central nervous system. Damaged synapses have exposed phosphatidylserine (PS), signaling for microglial-mediated phagocytosis [83]. An efficient phagocytosis of damaged synapses halts the spreading of the damage and may underlie synaptic resilience in DRNC [53]. Increasing TREM2 levels reduces amyloidosis, rescues synaptic loss, and improves water maze performance of APP/PS1 (double transgenic mice expressing a chimeric mouse/human amyloid precursor protein [Mo/HuAPP695swe] and a mutant human presenilin 1 [PS1-dE9]) mice [54, 55]. Inappropriate activation of microglia, however, may exacerbate neurodegeneration [84]. Aged (at an age of 18 months) mice with loss of TREM2 (Trem2−/− mice), however, have increased dendritic spine density, show superior cognitive performance and age-related synaptic/cognitive resilience [85]. Through microglial PKC, TREM2 may promote activation of reparative/regenerative microglial subtypes and remyelination and repair in the brain [86, 87]. On the other hand, loss-of-function TREM2 mutations have also been reported to result in Nasu-Hakola disease, progressive presenile dementia with bone cysts [88] and a 2-4-fold increase in the risk of development of AD. It is not clear what may contribute to the contradictory observations.

Myocyte enhancer factor 2 (Mef2)

Mef2 family of transcription factors may play a role in promoting cognition and cognitive resilience. Higher Mef2C is induced by neuronal activity and observed in resilient individuals, driving environmentally induced cognitive protection [52]. Overexpression of Mef2 family transcription factors in neurons of a mouse tauopathy model has been shown to be sufficient to improve cognition independent of tau pathology [52].

Phospholipase A2 group IVE (Pla2g4e)

The cytosolic Pla2g4e decreases in the brains of late-stage AD patients. Overexpression of Pla2g4e in the hippocampal neurons of AD mice was sufficient to completely restore cognitive function and increase spine number without affecting amyloid or tau pathology [89].

Lysine demethylase 6A (Kdm6a)

In transgenic animal models, the presence of an additional X chromosome either in males or females improves cognition, cellular viability, and Aβ-related mortality [90], due to the gene Kdm6a. Kdm6a overexpression attenuated Aβ-induced neurotoxicity and cognitive impairment [84].

Cognitive resilience is also dynamic and sensitive to diverse factors and pharmacological therapeutics and modifiable over the lifespan. Cognitive/synaptic resilience is sensitive to lifestyle changes [91] that promote neurotrophic activities [92] and reduce inflammation [27]. However, improved synaptic/cognitive resilience that persists through late-life-style changes are mild in strength, often insufficient to overcome injuries and/or disorder pathology, especially for those who need it the most. What is exciting is the emerging evidence that cognitive/synaptic resilience can not only be built [12], but also be enhanced through exogenous pharmaceuticals. Treatments that modulate neurotrophin levels have acquired a great deal of interest in preventing neurodegeneration and promoting synaptic resilience and neuro-regeneration.

Pharmacological management of cognitive/synaptic resilience represents a novel strategy in the fight against AD. Promoting cognitive resilience involves a combination of both mechanisms: enhancing synaptic resilience and preventing neural and synaptic degeneration. Restoration of cognitive/synaptic resilience pharmacologically can be achieved through several novel approaches. For instance, promoting synaptic resilience through increasing BDNF levels has yielded encouraging results [93]. Bryostatin-1, a relatively selective PKCε activator, consistently enhanced the hippocampal levels of BDNF and increased the number of dendritic spines in several animal models, including Tg2576 [32]. In aged 3x Tg-AD mice, neural stem cell (NSC) transplantation rescues cognition through BDNF-mediated robust enhancement of hippocampal synaptic density, without altering Aβ and tau pathology [94]. Recombinant BDNF mimics the beneficial effects of NSC transplantation. Loss-of-function studies showed that beneficial effects of NSC transplantation on cognition and hippocampal synaptic density were eliminated by knockdown of NSC-derived BDNF [94]. In 5xFAD mice crossed with mice expressing BDNF under the GFAP promotor, astrocytic expression of BDNF rescued reduced spine density in the frontal cortex and hippocampus PSD-95 and synaptophysin (synaptic markers), and memory performance [93] including novel object recognition, Y-maze, and passive avoidance tests, in the 5xFAD mice. Viral delivery or overexpression of BDNF in a variety of AD models has also been found to improve cognition, independent of any effects on amyloid or tau neuropathology [95, 96]. BDNF expression/activity may also be enhanced by other agents, such as ROCK (Rho kinase) inhibitors [97], and other PKCε activators. 7,8-Dihydroxyflavone (7,8-DHF) a potent small molecular TrkB agonist with poor oral bioavailability, has been found to promote BDNF and GDNF activity, reduce tauopathy and amyloidosis, and improve cognition in APP/PS1 mice [98]. Clathrin-nanoparticles delivering BDNF to hippocampus have also been found to enhance neurogenesis and cognition in HUIV/neuroAIDS animal models [99].

Concluding Remarks and Future Perspectives

Cognition, operation of the mind, is one of the most fearful abilities to lose. Shifting/switching neurodegeneration in the brain to neuro-regeneration has recently emerged as a novel therapeutic strategy in AD therapeutics. Neurodegenerative diseases, although highly complex depending on the brain tissues affected, are characterized by breakdown of connection and communication between neurons, through progressive degradation of synapses, axons, and eventual neuronal death [100] (see Outstanding Questions). Recent advances in AD therapeutic development indicate an essential role of synaptic integrity and neurotrophic activity in the progression of and recovery from AD. The major goal of neuro-regenerative therapy is to stop the degeneration of otherwise healthy neurons and promote regeneration/repair [101]. Importantly, promoting endogenous neuro-regeneration and cognitive/synaptic resilience offers a rare window/opportunity to reveal and achieve lifetime good cognition despite severe DRNC and aging, through pharmacological shift [44, 52, 85]. For example, a genetically modified form of LIMK1, a serine/threonine kinase that regulates actin polymerization via phosphorylation and inactivation of the actin binding factor cofilin, with an inserted “molecular switch” enables administration of rapamycin to turn it on and off inside the brain [102]. In aged animals with cognitive decline, this switch activation enhances synaptic functions and cognition [102].

Outstanding Questions.

What determines the dynamic balance between neurodegeneration and neuro-regeneration in the brains?

Is a single factor involved in “switch-off” brain neuro-regeneration and “switch-on” brain neurodegeneration?

Would loss of neuro-regeneration and synaptic resilience at particular brain networks be the sufficient and necessary conditions for a variety of neurodegenerative disorders?

Why are aging and AD accompanied by a loss of cognitive resilience in many individuals?

Would shifting neurodegeneration to neuro-regeneration be essential and sufficient to reverse the progression rate in Alzheimer’s dementia?

Therapeutic approaches with neurotrophins have been limited by sufficient delivery, lack of knowledge of optimal neurotrophic activity in human brains for an effective AD treatment and an oral formulation in development. While it has been well established that BDNF plays an important role in synaptogenesis, synaptic maturation, learning and memory and that its deficits lead to cognitive impairment among other brain dysfunctions. Clinical trials using recombinant BDNF have been disappointing, most likely due to poor delivery and/or a short half-life of BDNF in vivo. Results of recent studies, including clinical trials of bryostatin-1, a PKCε activator, are impressive [10]. Smaller molecules with similar efficacy but more desirable pharmacokinetic features may be developed in the future.

Although some new developments like these shine light on the potential of shifting neurodegeneration to neuro-regeneration, further development is badly needed for effective AD therapeutics with clinically meaningful benefits on cognitive functions. Identifying the mechanisms underlying neurodegeneration/neuro-regeneration and cognitive/synaptic resilience affords us not only the potential to better understand how the brain naturally adapts and responds to the presence of pathology, but also a promising pathway to a successful management of AD through pharmacology. This may change the current belief that no neurodegenerative disease is curable [103].

Highlights.

• No clinically effective therapeutics for Alzheimer’s dementia (AD) are currently available.

• The recently approved monoclonal antibodies for AD are rather limited in improving cognitive functions in AD, despite significant safety issues.

• Balance between neurodegenerative and neuro-regenerative in the brain are dynamic, depending on brain injury and activity and regulation of several neuronal signal pathways.

• Recent clinical trials have demonstrated the emerging concept that shifting/switching neuronal/synaptic degeneration to regeneration is achievable and can rescue cognitive functions and prevent dementia progression in AD patients.

• Pharmacological shift from neurodegeneration to neuro-regeneration represents a novel effective cognition-therapeutic in AD patients and preventive compound in preclinical AD individuals through building-up of cognitive resilience.

Glossary

AD

Alzheimer’s disease, the leading type of dementia. It begins with mild memory loss, progressing to loss of capacities in language, thoughts, and decision-making

BDNF

brain-derived neurotrophic factor promotes synaptogenesis, synaptic repair, neurogenesis, and neuronal survival

DAD

demented with AD pathology

DAG

diacylglycerol functions as a second messenger in many cellular processes

Dementia

a condition of progressive loss of cognitive functions, especially with impairments of memory, abstract thinking, and decision-making

DRNC (dementia-related neurologic changes)

high levels of β-amyloid and tauopathy in the brains, hippocampal sclerosis, microvascular lesions, and APOE genotype

ERK

extracellular-signal-regulated kinases are part of signaling cascades that transmit signals from many extracellular agents to regulate cellular processes

GAP-43

growth associated protein 43, a PKC substrate, is a crucial component in neuronal growth/development, axonal regeneration, and learning-associated neural plasticity

GDNF

glial cell-derived neurotrophic factor that promotes the survival and differentiation of many types of neurons, including dopaminergic neurons

MARCKS

myristoylated alanine-rich C-kinase substrate is a filamentous actin-across-linking protein

NDAD

non-demented with AD pathology

Neurodegeneration

a progressive loss of neuronal structures, from synapses to neural atrophy and death. Neurodegenerative disorders are cognitive and behavioral abnormities due to brain degeneration. AD is the leading neurodegenerative disorder

Neuro-regeneration

regrowth or repair of neural structure and synaptic connection, with a consequence of cognitive recovery from neurodegenerative disorders and neuronal injuries

NFTs

neurofibrillary tangles, intracellular tangles of hyperphosphorylated tau

NPs

extracellular neuritic Aβ plaques