Anti-Alzheimer’s Natural Products Derived from Plant Endophytic Fungi

Alzheimer’s is the most common cause of dementia worldwide and seriously affects patients’ daily tasks. Plant endophytic fungi are known for providing novel and unique secondary metabolites with diverse activities. This review focuses primarily on the published research regarding anti-Alzheimer’s natural products derived from endophytic fungi between 2002 and 2022. Following a thorough review of the literature, 468 compounds with anti-Alzheimer’s-related activities are reviewed and classified based on their structural skeletons, primarily including alkaloids, peptides, polyketides, terpenoids, and sterides. The classification, occurrences, and bioactivities of these natural products from endophytic fungi are summarized in detail. Our results provide a reference on endophytic fungi natural products that may assist in the development of new anti-Alzheimer’s compounds.


Introduction
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide that affects memory, thinking, and behavior and even interferes with daily tasks. The abnormal accumulation of beta-amyloid and phosphorylated tau proteins and nerve cell degeneration are deemed to play key roles in Alzheimer's disease [1,2]. According to the latest WHO report, the number of people suffering from dementia worldwide in 2010 was about 35.6 million, while the figure could be triple this by 2050 [1]. Age is the biggest risk factor for Alzheimer's dementia, which dramatically increases the incidence and death rate of Alzheimer's dementia and contributes to a heavy burden on families and society. The incidence of dementia was 5.0-13.1% for people over 65 years old, while this number increased to 33.2% as the age rose to over 85 years of age, and the death rate increased by 33-51% for people over 65 years of age and by 78% for people aged 80 and older [3]. Only a few therapeutic agents have been made clinically available for this disease, such as memantine, donepezil, rivastigmine, tacine, galantamine, and aducanumab [4][5][6]. These drugs can relieve AD-related symptoms for mild cognitive impairment, but are incapable of preventing disease progression to obtain ideal treatment effects [7]. Thus, it is critical to develop new treatments for AD to prevent and delay the progression of the disease, improve cognition, and reduce the behavioral disorders of patients with AD.
Endophytic fungi were first identified in plants in 1809 [8]. They are microorganisms that reside in the tissues of healthy plants for part of or all of their life cycle without causing apparent infection in the host plant. Some endophytes provide new bioactive compounds with unique structures containing alkaloids, phenols, lactones, quinones, ent AChE inhibition with IC50s of 0.056 ± 0.003, 0.088 ± 0.005, and 0.140 ± 0.007 μM, respectively [19].
A chemical study of the endophytic fungus Colletotrichum gloeosporioides collected from the leaves of Michelia champaca led to the isolation of a new compound, 2-phenylethyl 1H-indol-3-yl-acetate (77), which exhibited moderate AChE inhibitory activity at 200 µg during a bioautography analysis [26].
A new macfortine alkaloid, chrysogenamide A (78), was identified from Penicillium chrysogenum No. 005, an endophyte from the root of Cistanche deserticola. Compound 78 showed no scavenging DPPH free radical activity at 100 µM, while it exhibited the inhibition of H 2 O 2 -mediated SH-SY5Y cell death by enhancing cell viability by 59.6% at 1 × 10 −4 µM, suggesting that 78 exhibited a protective effect on neurocytes via oxidative stress-mediated cell death in SH-SY5Y cells rather than through antioxidant activity [27].
Chemical research on Neosartorya fischeri JS0553 associated with Glehnia littoralis produced two known alkaloids: fischerin (126) and pyripyropene A (127). The investigation of the mechanisms for glutamate-induced HT22 cell injury revealed that 126 could inhibit Ca 2+ influx, ROS, and the phosphorylation of JNK, ERK, and p38 to exert conspicuous neuroprotection [22].
The study of Talaromyces sp.
A study on Xylaria sp. HNWSW-2 collected from the stem of Xylocarpus granatum led to the isolation of astropyrone (150), which diaplayed weak anti-AChE activity with an inhibition rate of 10.4% at 50 µg/mL [46].
A chemical study of Chaetomium globosum associated with the seeds of Panax notoginseng led to the isolation of chaetomugilins A (153) and D (154). Neither showed antioxidant activities with an EC50 greater than 100 μg/mL in DPPH free radical scavenging [17].
A study on Xylaria sp. HNWSW-2 collected from the stem of Xylocarpus granatum led to the isolation of astropyrone (150), which diaplayed weak anti-AChE activity with an inhibition rate of 10.4% at 50 µg/mL [46].
A chemical study of Chaetomium globosum associated with the seeds of Panax notoginseng led to the isolation of chaetomugilins A (153) and D (154). Neither showed antioxidant activities with an EC 50 greater than 100 µg/mL in DPPH free radical scavenging [17]. Molecules 2022, 27, x FOR PEER REVIEW 10 of 32        [31].
A detailed chemical study of Phomopsis sp. 33#., an endophytic fungus from Rhizophora stylosa, led to the discovery of four new compounds, phomopsichins A-D (194)(195)(196)(197), and the known compound phomoxanthone A (198). Compounds 194-198 showed weak inhibitory activities against AChE with an inhibitory rate from 2.7% to 38.4% for a concentration of 250 µM and displayed weak scavenging DPPH activity with an inhibitory rate from 17.0% to 52% at 1 mM [54].
A detailed chemical study of Phomopsis sp. 33#., an endophytic fungus from Rhizophora stylosa, led to the discovery of four new compounds, phomopsichins A-D (194)(195)(196)(197), and the known compound phomoxanthone A (198). Compounds 194-198 showed weak inhibitory activities against AChE with an inhibitory rate from 2.7% to 38.4% for a concentration of 250 µM and displayed weak scavenging DPPH activity with an inhibitory rate from 17.0% to 52% at 1 mM [54].
Research on Aspergillus terreus (No. GX7-3B) related to a branch of Bruguiera gymnoihiza
A chemical assay for Talaromyces aurantiacus demonstrated the separation of two new compounds: talaromycins A (299) and B (300). The IC 50 of 299 for AChE inhibition was 12.63 µM [73].
Investigation into a co-culture of endophyte Epicoccum sp. YUD17002 and Armillaria sp.
A study on Pseudofusicoccum sp. J003 from the mangrove species Sonneratia apetala Buch.-Ham led to the separation of the new sesquiterpene, acorenone C (375), which exhibited moderate activity against AChE with a 23.34% inhibition ratio at 50 µM [85].
Nigrosirpexin A (383) was collected from a co-culture of Nigrospora oryzae and Irpex lacteus. This compound showed an AChE inhibitory capacity with a ratio of 35% at 50 µM [87].
A study on the Aspergillus sp. YXf3 of Ginkgo biloba found an irregular C18 norditerpenoid, aspergiloid I (439), which did not exhibit antioxidant properties or AChE inhibition at 50 μg/mL [97].   (Figure 18), were identified from culture extracts of Aspergillus oryzae associated with the marine red alga Heterosiphonia japonica. All the compounds exhibited a low capacity to modulate AChE with inhibitory rates from 0.4%-19.8% at 100 µg/mL [98].