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Global Translational Medicine Ocular changes in Alzheimer’s disease

in 90% of AD cases and is the earliest pathological sign alterations occurred in the healthy group with high
of disease progression. 29,58 Post-mortem studies on the neocortical plaque burden compared to the healthy group
brains of AD patients revealed a reduction in vascular with low neocortical plaque burden suggesting that retinal
density and more tortuous vessels described as exhibiting vascular changes occur in the early neocortical plaque
kinking and looping characteristics. Moreover, research deposition stage when cognition is not yet affected. 67
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on a transgenic mouse model of AD (TgCRND8) showed There is also evidence suggesting that Aβ burden is
a correlation between increasing Aβ accumulation with responsible for the vascular changes in the retina. First,
increased tortuosity and decreased vascular density. 60
increased levels of Aβ deposition in the retinal blood
Other studies identified disruption of the BBB, vessels were correlated to the degeneration of retinal
which impairs the clearance of Aβ from the brain. 61,62 capillaries. In addition, a substantial 50% reduction of
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Specifically, pericyte loss and downregulation of the low- platelet-derived growth factor receptor beta (PDGFRβ)
density lipoprotein receptor-related protein-1 (LRP-1) are was correlated with an increased Aβ burden in the retinal
proposed to contribute to BBB disruption as observed in microvasculature. This finding is consistent with a study
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AD patients and mouse models. 61,62 Aβ40 and Aβ42 have on post-mortem human retinas that found decreased
been identified in pericytes, which can trigger degeneration PDGFRβ signaling in AD correlating to increased retinal
of pericytes resulting in increased permeability of the vascular Aβ42 burden and Aβ plaques in the brain.
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BBB. 61,62 In addition, a study using mouse models revealed PDFRβ signaling is responsible for the recruitment of
that LRP-1 facilitated the removal of Aβ40 via the BBB. pericytes, thereby influencing the integrity of the blood-
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Therefore, impaired LRP-1 and pericyte loss may cause Aβ tissue barrier. Accelerated pericyte degeneration has also
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to accumulate and form plaques. It is difficult to visualize been observed with the presence of Aβ deposition in retinal
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the microcirculation in the brain in vivo; therefore, microvasculature. The pericyte and PDGFRβ loss may
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visualizing the retina could be used to estimate cerebral indicate a compromised BRB. Downregulation of tight
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microvascular pathology. 29 junction proteins located between the endothelial cells in
3.5.2. Changes in retinal vasculature the retinas of AD patients also contributes to impairment
and increased permeability of the BRB. An impaired BRB
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There is evidence that vascular pathology in the brain is could lead to increased accumulation of Aβ, which may
mimicked in the retina. For example, in patients with cause further damage to the BRB, perpetuating a vicious
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cerebral amyloid angiopathy, retinal Aβ plaques were pathological cycle.
also found surrounding or within the vasculature. The
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first study that observed retinal vascular abnormalities The mechanism behind vascular changes in the brain
in AD patients noted narrowed veins and reduced blood has been researched, and it can be expected that similar
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flow rate using a laser Doppler instrument. Similar processes cause changes in the retinal vasculature. In
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observations have also been reported, including more cerebral amyloid angiopathy, the deposition of Aβ on the
tortuous and sparser vessels in AD patients compared to walls of the blood vessels causes narrowing of the vessels
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control individuals. Schematic representation of these and occlusion leading to reduced blood flow. Vascular
changes can be found in Figure 3. In addition, a study collagen deposition also occurs with AD pathology,
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using a transgenic mouse models of AD discovered retinal contributing to reduced blood flow and the presence of
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capillary degeneration that reached significance when mice more tortuous vessels could also be an underlying factor.
were 8 months old, with higher susceptibility in males than Aβ also binds to and sequesters vascular endothelial growth
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females. Older age was correlated with increased retinal factor (VEGF) in plaques. Since VEGF is responsible for
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capillary degeneration in healthy mice; however, the extent angiogenesis, reduced circulating VEGF levels could lead
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was greater in the AD mice. To examine the association to fewer blood vessels and reduced vascular density.
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between AD-like pathology and vasculature alterations in These pathological mechanisms in the brain are predicted
the retina independent of age-related changes, transgenic to cause similar abnormalities in retinal vasculature. 64
AD mice in young, middle-aged, and old-age groups were 3.5.3. Alterations in the choroid
compared to healthy age-matched controls. Notably,
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alterations in the superficial and deep retinal vascular The retina has two vascular systems. The inner retina blood
plexus were accelerated in the AD mice compared to supply is from the central retinal artery and its branching
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the controls. Furthermore, a correlation was observed vessels, where the capillaries have a 1:1 endothelial-to-
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between retinal vascular changes and neocortical amyloid pericyte ratio, resulting in greater blood flow regulation.
plaque burden assessed using PET neuroimaging in live The outer retina is supplied by choriocapillaris from the
human participants. Interestingly, greater retinal vascular choroid which is a highly vascular tissue found between
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Volume 3 Issue 3 (2024) 8 doi: 10.36922/gtm.4094