Abstract
Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD.
Highlights
The number of elderly individuals with neurodegenerative disorders such as Alzheimer’s disease (AD) has expanded dramatically [1]
In order to investigate the integrity of the microvasculature in AD and ND control groups, brain sections were stained with collagen IV (Figure 1A–D) and the total capillary density for each case was determined (Figure 1E–F)
The average gray matter capillary density was highest in the AD group and lowest in the YO-NPC group, these differences did not attain a level of statistical significance (Figure 1E)
Summary
The number of elderly individuals with neurodegenerative disorders such as Alzheimer’s disease (AD) has expanded dramatically [1]. Alzheimer’s disease is an age-associated multisystemic syndrome. Cardiovascular disease (CVD), the most prevalent cause of morbidity and mortality [2], has long been associated with vascular cognitive impairment (VCI) and represents a potential contributing factor to AD development [3,4,5,6]. Cerebral amyloid angiopathy (CAA) plays a major role in brain hypoperfusion and dysfunction. Brain perfusion is further damaged by CAA due to a compromised interstitial fluid drainage resulting from the destruction of the perivascular spaces by the accumulation of amyloid [25]. In addition to all these pathological changes, cerebral hypoperfusion promotes vascular inflammation [4] and the expression of hypoxia-inducible and pro-angiogenic factors [28]. The emergence of anti-angiogenic molecules, including Ab peptides [29], may counterbalance activation of vascular remodeling and repair functions [4,30]
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