Page 23 - AN-3-4

Advanced Neurology Anticoagulants as neuroprotective therapeutics

enabled the determination of the atomic structures of Aβ which exhibit two distinct filament types that differ
and tau amyloids in human brain inclusions. Both types of mainly in their protofilament packing. In sporadic AD,
4
4
misfolded proteins exhibit self-replicating conformations, type I filaments are predominant, while type II filaments
4
characteristic of prions, which allow their self-perpetuating dominate in familial AD. Aβ filaments are present in both
spread and deposition throughout the brain. 2-4,37 Thus, parenchymal amyloid plaques, which are enriched with
AD can be considered a double-prion proteopathy. 3,4,37 Aβ42, and in deposits within blood vessel walls, where
4,43
In the AD brain, the generation and deposition of Aβ Aβ40 is more prevalent. Oligomers of both Aβ40 and
are typically the first major pathogenic event associated Aβ42 form small, soluble, and non-fibrillar assemblies,
with inflammation, neurovascular dysfunction, synapse which interact with the membranes of synapses, neurons,
loss, neuronal death, and cognitive decline. 2-6,10,11,14,15,27 An and glial cells, contributing to their pathogenicity within
imbalance between Aβ production and clearance, leading the brain parenchyma. The early formation of toxic Aβ
43
to the accumulation of Aβ in brain tissue, is believed to oligomers is thought to originate in the thalamus, from
be crucial in the pathology of Aβ. 2,3,5,35-37 The occurrence where they may spread to other brain regions, particularly
45
of NFTs, predominantly observed in the hippocampus and the neocortex and hippocampus, as the disease progresses.
secondarily in the cortex, usually follows Aβ accumulation These brain parts are key centers of information processing
46
and signals the onset of neurodegeneration and brain for cognitive, behavioral, and motor skills. During the
atrophy, which strongly correlates with cognitive decline. 5 early stages of AD, both vascular and parenchymal Aβ
deposition, as well as neuronal hyperactivity, synapse
3.1. Aβ pathology and neuron loss, and the decline of cognitive abilities, are
In a healthy brain, native Aβ is believed to contribute to concentrated in these brain areas. 36,43,46
proper nervous system function, the integrity of the BBB, Around parenchymal Aβ plaques, which grow in
and pathogen defense. 14,15 However, in the diseased brain, size and number outside neurons over the course of
Aβ monomers are increasingly generated by the proteolytic years, significant neuronal changes occur. The highly
47
cleavage of the membranous Aβ precursor protein (APP) aggregated Aβ that forms the plaque core is surrounded
through the amyloidogenic pathway. 2-5,10,15,35,38 In this by parenchymal areas where synaptic links between
process, APP is sequentially cleaved by β-site APP- neurons have been lost, and axons display abnormal
cleaving enzyme 1 (BACE1) and the γ-secretase complex, swellings known as dystrophic neurites. Each amyloid
47
generating Aβ, which is released into the extracellular plaque contains hundreds of axons with dystrophic
space. Mutations, especially in the Aβ region of the neurites, which serve as hotspots for the intracellular
APP gene or in presenilin genes that encode γ-secretase accumulation of tau and APP. Time-lapse imaging of
47
subunits, result in misfolded Aβ proteins that adopt a single axons in live mice has revealed that dystrophic
self-replicating, β-sheet-rich oligomeric structure. 2-4,42 neurites impair axonal transport between the neuron’s cell
This APP processing through the amyloidogenic pathway body and synaptic terminals, disrupting the propagation
occurs in microglia, astrocytes, oligodendrocytes, and of action potentials. As a result, long-range axonal
47
particularly neurons, 2,3,20,38,43 as well as in the platelets of AD connectivity is compromised, leading to dysfunction
patients. Aβ’s prion-like feature triggers the misfolding within the nervous system in the affected areas. One
44
47
of the additional native protein, 2-4,37 perpetuating its of the earliest predictors of cognitive decline in AD is
spreads in the brain spatiotemporally through Aβ seeds, synaptic dysfunction, which involves reduced plasticity in
which consist of small amounts of misfolded Aβ. 3,4,37 Aβ forming new synaptic connections and synapse loss. 2,5,14,36
monomers polymerize into various assemblies, including The presence of Aβ plaques is also closely linked to
soluble oligomers and protofilaments, which deposit as neuroinflammatory events, as the association between
amyloid filaments between neurons, eventually forming Aβ plaque formation and microgliosis is strong, while the
insoluble Aβ plaques or senile plaques. 2-4,15,38,43 Cryo- correlation with neurodegenerative changes is relatively
electron microscopy studies have revealed that Aβ weak. 20,38,42,47 This observation is consistent with recent
plaques contain a mixture of filaments, some of which studies in mouse models and in familial AD, where Aβ
42
are branched, forming parallel and lattice-like structures aggregation has been shown to be kinetically decoupled
43
interspersed with other brain materials. Among the from neurotoxicity. Neurodegenerative events appear to
43
more than 100 possible Aβ isoforms – exhibiting variable occur after Aβ seeding activity has reached saturation
lengths and chemical modifications – the isoforms with 40 but before Aβ deposition reaches critical (half-maximal)
(Aβ40) and 42 (Aβ42) amino acids are the predominant levels. This temporal dissociation suggests a prion-like
42
neurotoxic types in AD. 3,4,20,38,43 Filament structures molecular mechanism for Aβ, similar to the bi-phasic
derived from Aβ consist of two identical protofilaments, progression observed in prion diseases. 3,37,42,48

Volume 3 Issue 4 (2024) 5 doi: 10.36922/an.3799